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Review

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

1
Laboratory of Physiology of Reticular Formation, National Institute of Neurology and Neurosurgery-MVS, Insurgentes Sur 3877, La Fama, 14269 Mexico City, Mexico
2
Epilepsy Clinic, Hospital General de México Dr. Eduardo Liceaga. Dr. Balmis 148, Doctores, 06720 Mexico City, Mexico
3
Departamento de Neurobiologia Conductual y Cognitiva, Instituto de Neurobiologia, Campus UNAM-Juriquilla, Universidad Nacional Autonoma de Mexico, 76230 Queretaro, Mexico
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8573; https://doi.org/10.3390/ijms21228573
Submission received: 12 October 2020 / Revised: 4 November 2020 / Accepted: 11 November 2020 / Published: 13 November 2020
(This article belongs to the Section Molecular Neurobiology)

Abstract

:
Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

Graphical Abstract

1. Introduction

Epilepsy is a chronic, recurrent and progressive neurological disease, which affects approximately 65 million people worldwide [1]. It is characterized by recurrent spontaneous epileptic seizures that result from abnormal and excessive electrical discharges. Despite many advances in epilepsy research, approximately 30% of all patients show drug-resistant epilepsy [2], which is defined as the persistence of epileptic seizures despite the application of an adequate and well-tolerated pharmacological treatment [3]. Temporal lobe epilepsy (TLE) is the most common form of epilepsy and often resistant to antiepileptic drugs (AEDs) [4,5].
The pathophysiological mechanisms that underlie the development of chronic epilepsy, or epileptogenesis, are still unclear [6]. The progression of the disease most likely involves a combination of neurological changes in the brain [7]. Finding novel therapeutic targets and developing effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression are priority objectives in preclinical research.
This review describes in detail the recent advances in the search for potential therapeutic targets for the treatment of epilepsy, with a special emphasis on the variety of signaling pathways (Wnt/β-catenin, mTOR and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (TRPV1 channel) and receptors (galanin and melatonin receptors) involved in the development and progression of the disease. We give the prospects of their application as a treatment not only for seizures or epilepsy but also for drug-resistant epilepsy.
Based on preclinical and clinical evidence, all of these targets have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity (protecting brain areas against seizure-related brain damage) and in modifying the progression of epilepsy (antiepileptogenic intervention). In this review, we choose these specific targets because, while some research with them has been done in relation with epilepsy, they have not been fully explored as potential therapeutic drugs that could help address the unsolved issue of drug-resistant epilepsy and develop more efficient drugs for the treatment of epilepsy.

2. Wnt Signaling Pathway

Since its discovery, the so-called Wingless/integrase-1 (Wnt) gene and its downstream signaling, have been related to fundamental biological processes, including embryonic development, neurogenesis, synaptogenesis and adult neural plasticity [8,9].
Three different branches of signaling pathways mediated by Wnt proteins have been identified: (a) the canonical pathway, also called the Wnt/β-catenin pathway, involves the stabilization of the proto-oncogene β-catenin [10,11,12]; (b) noncanonical (β-catenin-independent) Wnt signaling or planar cell polarity (PCP) pathways, which are required to establish tissue polarity of many epithelia [12,13,14]; and (c) the Wnt/Ca2+ pathway, which stimulates the intracellular release of Ca2+ and activates calcium-dependent mediators [12,15,16].
The Wnt/β-catenin signaling pathway is the most characterized signaling cascade and its activation has been prominently involved in regulating cell differentiation and proliferation.

2.1. Wnt/β-Catenin Pathway

In steady-state or in the absence of Wnt stimulation, cytoplasmic levels of β-catenin are low because of its degradation by a cytoplasmic destruction complex, formed by axis inhibition protein (Axin), Adenomatous Polyposis Coli (APC), constitutively active Casein Kinase-1α (CK-1α) and Glycogen Synthase Kinase 3β (GSK3β) [17,18,19]. β-catenin is phosphorylated by CK-1α and GSK3β, resulting in recognition and ubiquitination, followed by proteasomal degradation [17,20] (Figure 1).
To initiate the Wnt/β-catenin signaling transduction pathway [9,10,12,21], Wnt proteins (lipid-modified, secreted proteins of approximately 400 amino acids) bind to cell surface receptor Frizzled (Fz; a seven-transmembrane receptor that contains a cysteine-rich domain) which forms the Wnt-binding site. In addition to Fz, other proteins act as coreceptors such as the single transmembrane low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Upon Wnt-Fz-LRP5/6 interaction, Axin is recruited to the phosphorylated tail of LRP5/6 by the scaffold protein Dishevelled (Dvl) which disassembles the destruction complex. Dvl inhibits the activity of the enzyme GSK3β, which prevents the phosphorylation of β-catenin and posterior ubiquitination. Under these conditions, β-catenin accumulates within the cytoplasm and translocates to the nucleus, where it will displace the Groucho transcriptional repressor and bind to the transcription factors such as DNA-bound T-cell factor/lymphoid enhancer-binding factor 1 (TCF/LEF) to finally activate the transcription of Wnt target genes (Figure 1). Several Wnt target genes are expressed in this process, including c-Myc, cyclinD1, Axin2 and Ca2+/calmodulin-dependent protein kinase type IV (CamKIV) [22,23].

2.2. Wnt/β-Catenin Pathway and Epilepsy

Several lines of evidence have shown that the Wnt/β-catenin pathway serves as a key bimodal regulator of neurogenesis, facilitating both positive and negative regulation of neuronal homeostasis [24]. In relation to epilepsy, the Wnt/β-catenin pathway has been involved with seizure-induced neurogenesis and neuronal death during the acute and chronic phases of epilepsy.
By different acute seizures models and epilepsy models, elevated expressions of Wnt/β-catenin pathway components have been found, which are associated with the increased neurogenesis and neuronal death commonly observed after seizures [25,26,27,28].
For example, chronic electroconvulsive seizures produced an upregulation of both Wnt2 expression and levels of β-catenin immunoreactivity in the subgranular zone of the adult rat hippocampus, showing that seizure activity regulates components of the Wnt/β-catenin pathway [25].
In another study, employing the amygdaloid kindling model, it was found that rats that received a major number of stimuli (45 stimuli) showed the highest levels of β-catenin in the cerebellum, suggesting the Wnt/β-catenin pathway as one of the mechanisms of generalized seizures generation [26].
Theilhaber et al. [27] investigated how functional pathways could be activated during hypoxic seizures by microarray profiling. They found a gene expression increase of several components of the Wnt/β-catenin pathway including genes for β-catenin (CTNNB1), inhibitory protein SFRP2 and transducer Dvl3; co-receptor LRP6; the β-catenin regulatory complex components CSKN1E, GSK3β, Axin2, and APC; and the genes for Frizzled ligands Wnt2, Wnt5a and Wnt10a. Thus, these increases of gene expression may reflect synaptic changes due to the activation of the Wnt/β-catenin pathway, in response to hypoxic seizures.
In an epilepsy model induced by kainic acid (KA), the Wnt/β-catenin pathway was activated by upregulation of the expression levels of its key regulators (Wnt3a, cyclin D1 and β-catenin) in a time-dependent manner, in the hippocampus of epileptic animals [29].
On the other side, it has been suggested that the Wnt/β-catenin pathway could also have a potential role in regulating seizure susceptibility and epileptogenesis.
Campos et al. [30] employed cre-loxP-mediated conditional mutagenesis to generate mutant mice with restricted deletion of β-catenin (Catnb conditional knockout mice, restricted to cerebral cortex and hippocampus). These mice showed, on the one side, missing hippocampal structures as well as cortical dysplasia and, on the other side, increased seizure susceptibility to pentylenetetrazole (PTZ). The above suggests that β-catenin-mediated signaling pathways are critically involved in controlling cortical development, seizure susceptibility and epileptogenesis.
Another study examined microRNAs (miRNA) expression/regulation of signaling pathways involved in epileptogenesis, after electrically-induced status epilepticus (SE) in rats, in a model of TLE [31]. It was found that, after the SE treatment, both significant upregulation and downregulation occurred of the miRNAs that target genes of the Wnt pathway [31], which suggests that silencing or activating specific miRNAs that target Wnt pathway genes could have therapeutic potential.
On the other hand, Yang et al. [28] investigated whether Wnt/β-catenin pathway is involved in the seizure-facilitating effects of reactive astrocytes after ischemia. They found that cerebral ischemia enhanced seizure susceptibility in the PTZ-kindling model and that reactive astrocytes are involved in this ischemia-increased seizure susceptibility [28]. More important is that the Wnt/β-catenin pathway was activated in Nestin-positive reactive astrocytes after ischemia and that depletion of β-catenin in reactive astrocytes could attenuate the ischemia-increased seizure susceptibility after PTZ kindling, indicating the requirement of β-catenin for seizure induction [28]. In general, Yang et al. [28] demonstrated the role of astrocytic Wnt/β-catenin pathway in facilitating seizure-induction after ischemia.
Pirone et al. [32] developed conditional knockout mice of the APC protein (APCcKO), generating an animal with high levels of β-catenin. These animals showed many of the signs and symptoms developed in infantile spasms (IS, a common childhood epilepsy syndrome) [33], such as neonatal spasms, abnormal EEG activity in neonates and adults and progression to spontaneous seizures [32]. Excessive β-catenin levels have been associated with aberrant dendritic and axonal branching, increased excitatory synapse density and altered synaptic maturation and function [34,35]. Such changes in vivo would be consistent with neural circuit hyperexcitability and increased seizure susceptibility. All of these previous results strongly support the impact of Wnt/β-catenin signaling in epilepsy [32].
The Wnt/β-catenin pathway also plays an important role in apoptosis, as Wnt pathway activation stimulates β-catenin to directly induce the expression of apoptotic-promoting proteins such as c-Myc and cyclin D [26,36,37]. These findings suggest this pathway as one of the mechanisms by which neurons ultimately die during chronic epileptic seizures, just as it was observed in the cerebellar neurons of rats chronically stimulated with the amygdala kindling [26], where higher activation of the Wnt/β-catenin pathway was associated with the increased presence of apoptotic markers such as c-Myc, cyclin D3, TUNEL and caspase 3 [26].
All these results highlight the importance of Wnt/β-catenin signaling in controlling seizure susceptibility, apoptosis, neurogenesis and potentially epileptogenesis in several animal models of epilepsy. Therefore, the modulation of Wnt/β-catenin pathway could have beneficial effects in protecting against neuronal damage and death following seizures [38].
Secreted glycoprotein Dickkopf-1 (Dkk-1) acts as a selective inhibitor of the Wnt/β-catenin pathway [39,40,41] which could contribute to the neuronal damage associated with TLE [38]. A correlation has been found between the induction of Dkk-1 and neuronal death in rats developing seizures in response to kainate injection, as well as a strong expression of Dkk-1 in the hippocampus of patients with TLE associated with hippocampal sclerosis (a common form of epilepsy associated with drug-resistance) [38], where the induction of Dkk-1 might represent a component of the sequence of events leading to neuronal death [42]. In addition, there was a reduction of β-catenin levels in the hippocampal nuclear fraction of these animals, suggesting that Dkk-1 inhibits the Wnt/β-catenin pathway, by limiting the amount of β-catenin available for nuclear translocation [38] and depriving neurons of the activation of a gene program that is essential for their survival [43]. In this way, antagonizing Dkk-1 was found to limit the extent of neuronal damage associated with TLE independently of its effect on seizure activity [38]. Pretreatment with either Dkk-1 antisense oligonucleotides or lithium ions reduced kainate-induced neuronal damage [38]. Lithium ions are known to rescue the Wnt/β-catenin pathway by inhibiting GSK3β, this is, by acting downstream of the Dkk-1 blockade [44].
For these reasons, Dkk-1 antagonists [38,45,46] or GSK3β inhibitors [38,47,48,49,50,51] could be promising therapeutic candidates for epilepsy. However, it is necessary to delimit the time window to suppress or enhance neurogenesis by the modulation of Wnt/β-catenin signaling, either at the beginning or once epilepsy has fully developed, in order to establish when modulation of the pathway may be the most beneficial as a therapeutic target in epilepsy.

3. The Mammalian Target of Rapamycin (mTOR) Signaling Pathway

The mammalian target of rapamycin (mTOR) is a kinase ubiquitously expressed that belongs to the phosphoinositide-3-kinase (PI3K) family [52], regulating cell growth, differentiation, proliferation and metabolism by participating in multiple signaling pathways [53]. Specifically, in the brain, it is involved in functions that can affect neuronal signaling and excitability, as well as axonal and dendritic morphology, neurotransmitter receptor expression and synaptic plasticity [53,54,55].
In mammalian cells, mTOR is encoded as a single gene whose protein product signals via two different complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [56,57]. Each complex possesses different substrates, cellular functions and sensitivity to rapamycin. In the case of rapamycin-sensitive mTORC1, it suppresses autophagy and its signaling is inhibited by rapamycin and its derivatives (allosteric mTOR inhibitors) [58]. Moreover, it promotes lipid, nucleotide and protein synthesis, as well as cell growth and cell proliferation via activation of S6K (1/2) and inhibition of the translation repressor 4E-BP1 (Figure 2) [53,59]. In fact, the phosphorylation of S6 and S6K1 is considered as a biomarker for mTORC1 activation in neurons [60] and an important contributor to the effects of mTORC1 hyperactivation [61].
On the other hand, rapamycin-insensitive mTORC2 is a key regulator of the actin cytoskeleton and is insensitive to any rapamycin treatment [53,58,59]. In addition, it promotes cell survival via activation of Akt/PKB (protein kinase B) (Figure 2) [62], which inactivates diverse pro-apoptotic factors [63,64].
Much of the available information regarding mTOR signaling in the brain focuses on mTORC1 as a crucial regulator of neuronal excitability since its involvement in the modulation of several processes such as: (1) cerebral cortical development [65,66]; (2) protein synthesis [67,68]; (3) cell differentiation, proliferation, growth, and survival [69,70,71,72]; (4) axonal sprouting, regeneration, and myelination [73,74]; (5) glial functions [75]; (6) dendritic morphogenesis [76]; (7) ionic and receptor channel modulation [68,77,78]; and (8) some forms of neuronal plasticity such as long-term potentiation, long-term depression, learning and memory [79,80,81]. However, changes in mTORC1 activity are known to result in increases in translation, transcription, autophagy, cell signaling, metabolism and altered cytoskeleton dynamics [82,83] that have been correlated with the pathophysiological development/progression of some psychiatric diseases and neurological disorders such as depression [84,85], schizophrenia [86,87], autism [88,89], Parkinson’s disease [90,91], Alzheimer’s disease [92] and epilepsy [93,94], among others.

mTOR Signaling and Epilepsy

Considering mTOR involvement in cellular functions influencing neuronal excitability, this signaling pathway could participate in the development of epilepsy (Figure 2), as it has been reported in both animal models of epilepsy and in human tissue samples resected from individuals with epilepsy.
Enhanced mTOR signaling in the brain was first identified in resected specimens from patients with tuberous sclerosis complex and focal cortical displasia [60,95], both considered as focal cerebral cortical malformations that usually cause drug-resistant seizures in children [96,97]. Later studies using different animal models of genetic and acquired epilepsies demonstrated that a hyperactivated mTOR seems to play a crucial role in epileptogenesis [98] and that mTOR inhibitors decrease the development of seizures preventing epileptogenesis-related mechanisms [99].
Zeng et al. [100] were the first to suggest that mTOR could be a potential therapeutic target for epilepsy. They used a mouse model of tuberous sclerosis complex and showed that early treatment with rapamycin not only inhibits the activation of mTOR but also delays astrogliosis and hippocampal pyramidal cell disorganization, preventing the development of epilepsy. Moreover, when rapamycin was administered in already epileptic mice, it can also suppress seizures.
Diverse studies have proven an increased mTOR activation in rodent models of TLE where seizures were chemically-induced by pilocarpine [101] or KA [102,103,104]. A similar effect was described in animals with acute PTZ-induced seizures [105] and in electrically-induced epileptic animals [106]. Particularly, Zeng et al. [102] showed a biphasic activation of mTOR that possibly correlates with the observed epileptogenic events: the first one occurring minutes/hours after the SE-induction and the second one 3–7 days after being induced.
Some experimental reports have suggested that a decreased mTORC2-dependent negative regulation of proapoptotic pathways may be responsible for acute seizure-induced neuronal death [107,108]. Recently, Talos et al. [109] showed that mTORC1 and mTORC2 are highly activated in surgically resected samples from drug-resistant TLE patients. In addition, they established for the first time two neuroprotective signaling pathways downstream from mTORC2. Their results suggest that the chronic use of rapamycin or its derivatives may also affect mTORC2 function. In addition, mTORC1 and mTORC2 seem to be activated in chronic rodent models of TLE [110,111].
All previous results support the notion that a hyperactivated mTOR signaling may contribute to epilepsy and that mTOR inhibitors could act as potential antiepileptogenic or antiepileptic treatments [112].
Treatment with rapamycin in models of epilepsy and acute seizure models, has demonstrated significant variability. In some cases, mTOR inhibition has mitigated acute or chronic seizures, and, in other models, the blockade of mTOR by rapamycin had minimal effect on seizures or epilepsy development [102,113,114,115,116], suggesting that the effects of rapamycin might only be restricted to certain experimental models and conditions [98,117]. This is a good reminder that there are both a vast number of downstream mechanisms that may mediate epileptogenesis and overlapping pathological mechanisms across the different existing types of epilepsy.
In clinical settings, mTOR inhibitors are effective and FDA approved for treating subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Muncy et al. [118] described for the first time the effectiveness of rapamycin in the treatment of a 10-year-old girl with drug-resistant epilepsy, reporting a significant reduction in seizure frequency. Later studies showed that everolimus, a rapamycin analog, was also effective in the treatment of tuberous sclerosis complex-related epilepsy by reducing the seizure frequency and the volume of the subependymal giant cell astrocytomas [119,120,121,122]. However, rapamycin and its derivatives display non-favorable pharmacokinetics with poor oral bioavailability, low blood–brain barrier (BBB) penetration, as well as slow accumulation in the brain [123,124].
Recently, two highly selective inhibitors have been developed: a mTORC1/C2 inhibitor (PQR620), which targets both mTOR complexes (mTORC1 and mTORC2) that shut down the feedback activation of the mTOR pathway, and a dual pan-PI3K/mTOR inhibitor (PQR530), which, in addition to mTORC1 and mTORC2, also inhibits PI3K, counteracting the feedback activation upstream of mTOR [53,125,126,127]. Both inhibitors seem to rapidly penetrate into the brain, reaching brain plasma levels of >1, and they are eliminated with a half-life of only ~5 h [125,126,127]. However, although PQR620 showed dose-dependent antiseizure efficacy [125], both PQR620 and PQR530 lack an antiepileptogenic effect, that is, they did not prevent or modify epilepsy in a post-SE model of TLE [128], in the same way that rapamycin did not show antiepileptogenic effect in this model [104]. In addition, administration of PQR530 inhibitor was associated with adverse effects, particularly loss of body weight [128].
Therefore, alternative pharmacological approaches to selectively modulate the mTOR pathway seem to be preferable for treating epilepsy. Based on the pharmacokinetics advantages and antiseizure efficacy, particularly of PQR620 inhibitor, it would be interesting to research the antiepileptic potential of mTOR inhibitors, both in chronic animal models of epilepsy and in drug-resistance epilepsy.

4. Zinc Signaling

Zinc constitutes one of the most abundant metal ions found in the human brain where it participates in neuronal and synaptic functions [129,130], also it can function as a catalytic factor, a structural component and a signaling mediator [129,130], both extracellularly and intracellularly [131,132,133].
Different transporter proteins exist to modulate and to maintain zinc homeostasis. The zinc transporters (ZnTs: subtypes 1–10) decrease cytoplasmic zinc by taking it out of the cell or by moving it into cellular organelles [134]. Of these transporters, the ZnT3 subtype is found in the synaptic vesicle membrane, and its principal function is to store zinc in the vesicles [135,136], while the ZnT1 subtype is found in the plasma membrane, and its function is to reduce intracellular zinc levels [137,138]. In the brain, the ZnT1 transporter is found in the cortex and hippocampus [139], while other subtypes such as ZnT4, ZnT5 and ZnT6 are also found in diverse brain areas [140,141].
The zinc-regulated and iron-regulated transporters’ (ZIP; subtypes 1–14) function is to increase the cytoplasmic levels by up taking zinc from cellular vesicles or from the extracellular space [132,142,143,144].
Metallothioneins (MTs; subtypes I–IV) are high affinity proteins to zinc which function as zinc’s temporary cytosolic store promoting its union to MTs during periods of increased zinc concentration [145]. The main subtype located in neurons, the MT-III protein, has been found in cerebral areas such as amygdala, cerebellum, cortex and hippocampus [146].
In the brain, it has been reported that zinc can induce or prevent neuronal injury depending on the cell type involved and of the zinc levels in those specific cell types [147,148,149,150]. Through the modulation of different receptors, such as the N-methyl-D-aspartate receptor (NMDAR) or the γ-aminobutyric acid A receptor (GABAAR), zinc is able to regulate both excitatory and inhibitory neurotransmission [151,152,153].
Interestingly, zinc can be released into the synapse along with glutamate, from glutamatergic neurons, during neuronal excitation [154,155,156,157,158]. These glutamatergic neurons containing zinc are mainly found in the hippocampus and the amygdala [153,159].
Additionally, zinc can also modulate the activity of several types of ion channels, such as potassium, calcium or sodium channels, and can modulate some membrane receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and glycine receptors [160,161,162].
Another receptor that interacts with zinc is the zinc-specific receptor/G protein-linked receptor 39 (mZnR/GPR39) [163,164,165]. This receptor is expressed in cerebral areas such as cortex, amygdala or hippocampus [166], and, upon its activation by zinc, it triggers an increase in Ca+2 release and consequently the activation of a series of intracellular signaling pathways [167].

Zinc, Seizures and Epilepsy

Zinc is necessary for maintaining the balance between neuronal excitation and inhibition, via modulation of a variety of targets. Thus, it is possible that zinc plays an important role in the pathophysiology of seizures and/or epilepsy.
At the human brain, the increased levels of metallothioneins I/II (MT-I/II) in the hippocampus of patients with drug-resistant TLE and TLE associated with tumor or dysplasia, suggest the involvement of MTs in these pathophysiologies [168]. In addition, deficiencies in plasma zinc levels have been associated with human epileptic disorders [169,170,171]. At flurothyl-induced model of recurrent neonatal seizures, there were changes in the expression of MTs and zinc transporters (ZnTs) [172,173,174,175].
On the other hand, ZnT-3 knockout mice are more sensitive to seizures caused by KA injection or hyperthermia due to their lack of synaptic zinc ions [176,177], indicating that a deficiency in synaptic zinc ions reduces seizure thresholds. The mZnR/GPR39 knockout mice also presents enhanced susceptibility to KA-induced seizures and increased seizure duration [178].
Potassium chloride cotransporter 2 (KCC2) is a neuron-specific chloride extruding transporter, responsible for hyperpolarizing currents mediated by GABAAR activation [179,180]. Loss of KCC2 function increase seizure susceptibility [181,182], and changes in KCC2 have been tightly linked to human epilepsy [183,184,185,186,187,188]. It has been observed that activation of the mZnR/GPR39 receptor leads to the upregulation of KCC2 surface expression and activity [164,189]. In addition, mZnR/GPR39 activation acts as an adaptive homeostatic response to abnormal excitatory activity (e.g., during epileptiform activity) that enhances the inhibitory drive by enhancing KCC2 activity [178,190]. Thus, by regulating neuronal excitability, ZnR/GPR39 activity can limit neuronal firing and consequently may play a role in epilepsy development and progression.
Besides, there are studies suggesting that seizure activity can be moderated via zinc administration [191,192,193]. However, some results are contradictory due to the type of epilepsy, the dose and the route of administration of zinc.
Of the first kind of studies, it is reported that zinc loading delayed kindled seizure induction, while zinc deprivation accelerated kindling [194]. Subsequently, it was found that zinc deficiency causes increased seizure susceptibility, while it is reduced by zinc loading [195,196,197,198,199]. In addition, the administration of zinc chelators such as clioquinol and TPEN increased the incidence of spontaneously generalized tonic-clonic convulsions [199]. Zinc infusion into the hippocampus delayed the development of behavioral seizures in a kindling model of epilepsy [193], while its oral administration reduced seizure duration and increased the latency of seizures induced by PTZ [200]. However, a proconvulsive effect was observed with zinc´s intracerebroventricularly pretreatment which decreased the threshold and increased the severity of seizures induced by PTZ [201].
In addition, it has been proposed that zinc could have a neurotoxic role where excessive zinc could impair the protein degradation pathway and might be a crucial factor mediating neuronal death [202]. In line with this, another study demonstrated that the pretreatment with a high dose of zinc exacerbated pilocarpine-induced seizures, whereas a medium dose of zinc reduced the severity of limbic seizures [203]. In appropriate doses, zinc plays an important role in mitigating seizures by suppressing oxidative stress, apoptotic activity and IL-1β levels, resulting in neuroprotective effects [203].
Furthermore, it has been proposed that activation of KCNQ channels by intracellular zinc may represent a strategy to survive cell excitotoxicity associated with seizures [204].
All of the above indicates the complexity of zinc signaling in epilepsy, with pro- or anticonvulsant effects, and in some cases neuronal neurotoxicity, most likely due to the differing zinc sources and also because zinc modulates a variety of ion channels and receptors. Therefore, further studies are necessary before suggesting zinc supplementation as a therapeutic strategy to treat seizures, epilepsy or drug-resistant epilepsy. In addition, it is necessary to continue to study new targets associated with zinc signaling to investigate if modulating these proteins will produce anticonvulsant or antiepileptogenic effects.

5. Carbonic Anhydrase

Carbonic anhydrases or carbonate dehydratases are zinc-containing metalloenzymes present in most living organisms. They play a crucial role in several metabolic pathways and in the pH balance of several body fluids and tissues by catalyzing the reversible hydration of carbon dioxide (CO2) and dehydration of bicarbonate (HCO3) in a two-step reaction [205,206,207] Equation (1):
CO 2   + H 2 O   CA HCO 3   +   H +
Carbonic anhydrases have been categorized into five classes: α (only one found in mammals), β, γ, δ and ε. Of the five different types, the alpha (α) class has received the most attention due to its role in human pathology. To date, the family of α-carbonic anhydrases comprises 16 different isozymes, identified with different catalytic activities, tissue distributions and subcellular localization (I–III, VII and XIII are cytosolic; IV and XV are glycosylphosphatidylinositol-anchored proteins; VA and VB are mitochondrial; VI is secreted into saliva and colostrum; IX, XII and XIV are transmembrane proteins; and VIII, X and XI have no catalytic activity) [205,208]. Specifically, only carbonic anhydrases IV, V, VII and XIV have been identified throughout the human and murine central nervous system (CNS) [209,210,211].
As previously mentioned, carbonic anhydrases play a key role in the control of pH by maintaining the intra- and extracellular balance between CO2, HCO3 and H+ at the level of the whole organism (for example, respiratory and renal functions), in the BBB, in neurons and glia and in the interstitial fluid in the brain [212]. In the brain, the activation of the GABAA receptor opens channels that are more permeable to Cl than to HCO3, leading to a membrane hyperpolarization and GABA-induced inhibition. However, as seen in epilepsy, a prolonged activation of GABAA receptors can provoke an excessive accumulation of Cl ions in postsynaptic neurons; this depolarizes the postsynaptic neurons since the intracellular HCO3 is constantly replenished due to the intracellular carbonic anhydrases activity. In conclusion, GABAergic transmission can exert both seizure-suppressing and seizure-promoting actions, respectively [213]. Other studies have also reported that brain carbonic anhydrases play crucial roles in long-term synaptic transmission and memory storage via a similar pathway [207,214].

Carbonic Anhydrase, Seizures and Epilepsy

Abnormal levels or activity of the membrane-associated carbonic anhydrases have been related with different diseases such as obesity (VA and VB), retinitis pigmentosa, glaucoma (IV and XII), cancer (IX and XII) and epilepsy (XIV) [215,216,217,218,219]. Considering that epilepsy is a neurological disorder related to an imbalance between inhibitory and excitatory neurotransmission [220,221], there is a high probability that epilepsy could also be associated with fast alterations in extracellular ionic composition [212,222].
The relation between carbonic anhydrases and seizures has been supported since the 1950s by several clinical and experimental studies reporting that carbonic anhydrase inhibitors such as acetazolamide [223,224], methazolamide [225], topiramate [226,227] and zonisamide [228,229] have anticonvulsant effects. This effect has been attributed to CO2 retention, secondary to inhibition of the red cell and brain enzymes. Moreover, other mechanisms have been suggested, involving: (a) a blockade of sodium channels and kainate/AMPA receptors; and (b) an enhancement of the GABAergic transmission [230]. However, the potential of the previously mentioned inhibitors in the treatment of epilepsy and other neurological disorders is not fully understood since the precise carbonic anhydrase isoforms involved remain unknown [231,232]. During the last decade, the carbonic anhydrase-VII isoform has become a validated target given its brain distribution (mainly expressed in regions as cortex, hippocampus and thalamus) [211,233,234] and its previously mentioned involvement in neuronal excitation by enhancing bicarbonate-driven GABAergic excitation during intense GABAA receptor activation. In this sense, Ruusuvuori et al. [235] conducted a study on carbonic anhydrase-VII knockout mice where they addressed the role of carbonic anhydrase-VII in HCO3-dependent depolarizing GABA responses and in the generation of experimental febrile seizures induced by hyperthermia. To date, this animal model has provided new opportunities to examine how this neuron-specific isoform modulates excitability.
Currently, the main scope is to design, synthesize and evaluate new carbonic anhydrase-VII inhibitors [236,237]. In this sense, De Luca et al. [238] performed a virtual screening to find such compounds. To do so, they built pharmacophore models from crystal structures of two well-known carbonic anhydrase inhibitors in complex with human carbonic anhydrase-VII. A merged pharmacophore model was obtained and, subsequently, a library of thousands of compounds was screened; new chemical entities displaying significant carbonic anhydrase inhibitory effects in the nanomolar range were identified. More studies are needed to complete the anticonvulsant profile of the new compounds in the treatment of febrile seizures [235]. However, the role that anhydrase-VII might have in drug-resistant epilepsy, if any, is still unknown.

6. Erythropoietin

The hormone erythropoietin is an ~30 kDa multifunctional glycoprotein that has a crucial role in erythropoiesis by preventing apoptosis and inflammation (caused by certain circumstances such as hypoxia, toxicity or injury), and by stimulating the proliferation of erythroid progenitors and the production of red blood cells in the bone marrow [239,240]. It has been detected in several tissues such as liver (during fetal development), kidney [241,242], heart [243], uterus [241,244] and brain [241,245]. In rodent and human CNS, erythropoietin is expressed in astrocytes and neurons while its receptor (EPOR; a transmembrane receptor member of the type I cytokine superfamily which is pre-formed as homodimers on the cell surface) is expressed in endothelial cells, microglia, astrocytes, oligodendrocytes and neurons [246]. The vast extension of hormone and receptor activity is related to endogenous potent neuroprotective effects [247,248,249,250,251,252].
The erythropoietin-mediated neuroprotective effects have been reported in diverse studies of ischemia, parkinsonism, brain trauma, seizures and epilepsy [253,254,255,256,257,258,259,260,261,262], as well as its therapeutic effects, in different neurological disorders, such as stroke [263], schizophrenia [264] and Parkinson’s disease [265], among others.
The neuroprotection induced by erythropoietin has been associated with several mechanisms, including: (1) neurogenesis [266]; (2) protection against glutamate-induced neuronal damage [267]; (3) antioxidant and anti-inflammatory activity by inhibiting the nuclear factor-KB (NFKB) [268]; (4) antiapoptotic activity [269]; (5) BBB protection [270]; and (6) microglia modulation [271]. In contrast, other studies have reported that erythropoietin augments neuronal activity via Ca2+ channels activation [272] and increases free cytosolic concentrations of Ca2+ [273]. This suggests that the erythropoietin-induced neuroprotective effect can only be produced under certain cerebral conditions.

Erythropoietin and Epilepsy

In acute seizures models (PTZ and KA), of induced SE (pilocarpine or electrical) and of TLE, the modulatory effect of erythropoietin has been suggested as a strategy able to: (1) reduce the seizure severity [274]; (2) protect against the BBB disruption and the subsequent microglial activation [260,275]; (3) prevent aberrant neurogenesis and granule cell dispersion [260,274]; (4) inhibit proinflammatory mediators [276]; (5) decrease neuronal death and apoptosis [260,277,278]; and (6) provide protective effects against epileptogenesis [260].
Based on the previously mentioned neuroprotective and anti-inflammatory effects of erythropoietin, some studies have focused on the antiepileptogenic ability of erythropoietin-derived mimetic peptides. In this direction, Seeger et al. [279] administered the peptide pyroglutamate helix B surface peptide (pHBSP) after the electrical induction of a self-sustained SE, observing enhanced hippocampal cell proliferation, neuronal differentiation and cell survival. However, the number of rats presenting spontaneous recurrent seizures was not modified. Simultaneously, Zellinger et al. [280] reported the effects of epotris, another erythropoietin-derived peptide devoid of erythropoietic activity. Here, they evaluated the histopathological consequences of electrically-induced SE, reporting limited in vivo effects on cell consequences caused by prolonged seizures. Future studies, using the appropriate animal model and the optimum treatment parameters, are necessary to support the erythropoietin-derived peptide mimetic design as a reliable therapeutic strategy to prevent the onset and progression of epilepsy.
Regarding to erythropoietin receptor, Sanchez et al. [252] suggested that optimal neuroprotection by erythropoietin requires an elevated expression of its receptor in neurons. This idea was later supported by Ott et al. [281], reporting the upregulation of erythropoietin receptors in specific hippocampal areas of a drug-resistant epileptic patient submitted to surgery. Some of the proposed mechanisms underlying this effect can be associated with erythropoietin’s ability to inhibit caspase-3 [282] and to activate JAK-2, ERK-1/-2 and Akt pathways; this activation is associated with elevated Bcl-XL levels in neurons [283]. In consequence, the increased amount of Bcl-XL can downregulate the expression of pro-apoptotic proteins such as Bax and Bid [284]. These results confirm that erythropoietin protects neurons and suggests that this can result in further suppression of neuronal apoptosis by regulating the balance between pro- and anti-apoptotic Bcl-2 family proteins.
The notion that seizure activity represents a condition that induces brain hypoxia (a discrepancy between an adequate supply of oxygen through blood vessels cells and consumption) and ischemia is well established [285,286]. Experimental evidence demonstrates that both processes enhance glutamate release [221,287,288] and facilitate neuronal cell death [289,290], membrane depolarization [291,292], subsequent epileptic seizures and overexpression of the MDR-1 gene that encodes the multidrug efflux transporter P-glycoprotein (condition associated with drug-resistance) [293,294]. In addition, this augmented expression of P-glycoprotein can also facilitate cell membrane depolarization as a consequence of increased amounts of intracellular free radicals and Ca2+ [295,296].
On the other hand, seizure activity is also known to activate the hypoxia-inducible Factor 1 (HIF-1), which modulates the expression of hypoxically regulated genes such as those encoding erythropoietin and the vascular endothelial growth factor (VEGF) [297,298,299,300,301]. These results suggest that, in addition to the erythropoietin neuroprotective properties, the overexpression of HIF-1α and VEGF in neurons can also be a mechanism of cerebral protection in epilepsy. Given the previous findings regarding the neuroprotective, anti-inflammatory and antiepileptogenic effects of erythropoietin, it is reasonable to suggest that the development of erythropoietin-derived mimetic peptides could be a therapeutic target to treat epilepsy and drug-resistant epilepsy.
As the human recombinant erythropoietin was approved by the FDA as a safe and highly effective compound in the treatment of anemia in adults and children with renal failure, cancer and prematurity [302], further studies are necessary to establish the protective effect of recombinant erythropoietin in the brain once the epileptogenesis process has started, without causing undesirable side effects.

7. Copines

Copines integrate a small family of evolutionary conserved proteins able to bind to phospholipids in a calcium (Ca2+)-dependent manner [303]. They are found in diverse eukaryotic organisms and are characterized by two C2 domains in the N-terminal region of the protein followed by an “A domain” in the C-terminal region of the same protein. Following the “A domain”, copines have a variable-length C-terminal domain, which may confer unique characteristics to the different copine family members [304,305,306]. To date, there are nine copines (1–9) identified in mammals, ubiquitously expressed in diverse tissues such as heart, lungs, spleen, kidneys, prostate and brain [305,307,308,309,310,311,312,313]. Although the precise function of copines in mammalian cells remains unclear, evidence suggests that they are involved in regulating signaling pathways [306], in membrane trafficking [314] and in morphogenetic processes associated with the maturation of retinal synaptic architecture [315].

Copine 6 and Epilepsy

Copine 6 (also known as N-copine (neuronal-copine)) expression is almost restricted to the brain and it was first identified by Nakayama et al. in 1998 [307]. In that study, they reported that, in the hippocampal neurons, copine 6 mRNA expression is upregulated by experimental induction of seizures (via kainate injection) in an NMDA-dependent manner or after long-term potentiation induction. Later studies not only confirmed that copine 6 is expressed in the brain, but it is also involved in the translation of initial calcium signals into dendritic spine morphology changes to promote synaptic plasticity [316,317]. However, the precise functional role of copine 6 in the brain is not yet fully understood.
Diverse studies have described that certain patterns of dendritic spine disruption (e.g., structure, function, distribution and connectivity) may lead to altered neuronal circuits and become an underlying cause of many psychiatric and neurologic diseases such as Fragile X and Down syndrome [318,319], autism [320], Alzheimer’s disease [321,322], Parkinson’s disease [323] and epilepsy [324,325], among others.
In the specific case of TLE, one of the main forms of drug-resistant epilepsy, clinical and experimental studies point out to the altered balance between inhibitory and excitatory circuits [220,286,326,327] as a factor that facilitates aberrant plastic changes among hippocampal cells due to the constant uncontrolled occurrence of seizures and the subsequent long-term potentiation of synaptic transmission [328,329]. Therefore, we can conclude that plasticity is not necessarily a positive process in epilepsy and elucidate a possible relationship between epilepsy and copine 6 based on the notion that this protein is involved in synaptic plasticity due to its association with long-term potentiation [307,330].
Almost two decades later, Zhu et al. [331] published the first study focused on the expression of copine 6 in the brain tissue of epileptic patients. Here, they performed quantitative real-time PCR, Western blot and immunofluorescence analysis to evaluate the expression and distribution of this copine in the brain tissue of drug-resistant epileptic patients and pilocarpine-induced epileptic rats. Their results are the first to show the following findings: (1) copine 6 expression is significantly increased in the epileptic brain of the drug-resistant patients; (2) copine 6 mRNA and protein are significantly increased once the animals develop pilocarpine-induced spontaneous recurrent seizures; and (3) copine 6 protein is mainly located in neurons. These data suggest a new therapeutic target for the treatment of drug-resistant epilepsy. Moreover, although increased expression of copine 6 is observed after epilepsy development, further studies are necessary to determine if copine 6 is also involved in the epileptogenesis process.
In addition, it was reported there exists an increased interaction of adenylate kinase 5 (AK5) with copine 6, in TLE patients and experimental epileptic rats, where the AK5-copine 6 complex could play an important role in regulating epileptic seizures and epileptogenesis [332], suggesting a new therapeutic targets for the treatment of epilepsy, particularly drug-resistant epilepsy.

8. The Complement System

The complement system is a group of sequentially reacting proteins that, upon activation, mediate a number of biological reactions important in host defense [333]. Nowadays, it is well accepted that complement is a critical part of the innate immune response, playing a key role in host homeostasis, inflammation and defense against pathogens [334].
The complement system is comprised of numerous soluble proteins and membrane expressed receptors and regulators that operate in plasma, in tissues, on cell surface and even within the cell [335,336]. It is composed of more than 40 proteins which activate a cascade of molecular events leading to multiple effector mechanisms to protect the host in response to a wide variety of stimuli (order of activation: C1, C4, C2, C3, C5, C6, C7, C8 and C9) [336].

8.1. Complement System Activation

The complement system can be initiated depending on the context by three distinct pathways: (a) classical; (b) lectin; and (c) alternative. Each of them leads to a common terminal pathway, a non-enzymatic pathway, in which the terminal components are recruited sequentially from the fluid phase to form a large pore, that disrupts the membrane to cause target lysis (Figure 3) [336,337].
The classical pathway activation is determined by the binding between antibody complexes and the complement factor C1 [333,337]; the lectin pathway activation is due to the interaction with certain class of carbohydrate residues from pathogenic microorganisms [333,337]; and the alternative pathway activation is determined by the presence of foreign surfaces uncommon to the host cells [333,337].
All these three pathways overlap in the cleavage of C3 into its active fragments (C3a and C3b), to later continue with the activation of the complement cascade and to lead to the formation of the active fragments of C5 (C5a and C5b) [333,338] and the final assembly of the Membrane Attack Complex (MAC), a transmembrane pore consisting of C6–C7–C8–C9 complement factors, which will allow targeted cell lysis (Figure 3) [333,339,340].
C3a and C5a are molecules known as anaphylatoxins associated with inflammatory response [338,341,342]. They have the ability to function as chemoattractants to recruit immune cells to the complement activation site promoting the release of inflammatory mediators [338,342,343]. The C5a anaphylatoxin exerts its effects through binding to the C5a complement receptor 1 (C5ar1), which belongs to the G protein-coupled receptors (GPCR) family [338,343,344].

8.2. Complement System and Epilepsy

Complement causes pathology when regulation fails, leading to excessive activation that drives inflammation and tissue damage, which may contribute to seizure generation and epilepsy development.
Gene expression studies have demonstrated overexpression of various complement proteins in surgically removed tissue from patients with TLE [345,346,347,348] as well as in rodent TLE models [348,349]. Specific genetic polymorphisms in the C3 promoter region of mesial TLE patients suggested the involvement of the complement system in the genetic susceptibility to febrile seizures and to epilepsy [347]. In addition, increased immunoreactivity of multiple complement factors, such as C1q, C3, C4 and MAC, have been documented on activated microglia and select neurons in brain tissue from TLE patients and rodent TLE models [348,350], where the presence of MAC strongly suggests complement cascade activation in epileptic tissue. Another important finding is that sequential intrahippocampal injection of individual proteins of MAC (C5b6, C7, C8 and C9) in awake-freely moving rats, induce both behavioral and electrographic seizures as well as neurodegeneration [351].
Animal studies using transgenic mice have shown that the complement system contributes to seizures. Thus, C3-deficient mice develop significantly fewer behavioral seizures following Theiler’s virus infection than wild-type mice [352], while, in C6-deficient rats, the kindling development was delayed [353].
In C5ar1-deficient mice, it was demonstrated that complement receptor C5ar1 contributes to the acute inflammatory response elicited by infiltrating immune cells following pilocarpine-induced SE [354]. These findings suggest multiple mechanisms for the protective effects of C5ar1 pharmacologic inhibition or genetic ablation [354,355].
In this sense, targeting the complement could be a novel viable therapeutic strategy in epilepsy. Specifically, the therapeutic potential of the inhibition of the C5ar1 has been studied. The inhibition of C5ar1 by PMX53 antagonist was found to have anticonvulsant effects in the 6 Hz and corneal kindling model (acute seizure models), as well as in the intrahippocampal kainate model (chronic seizure model) [355]. Furthermore, inhibition of C5ar1 after pilocarpine-induced SE, or its genetic deletion, lessened seizure magnitude, protected hippocampal neurons from degeneration and reduced SE associated mortality [355]. It has been suggested that inflammatory cytokine expression and modulation of microglial potassium channels are affected by C5ar1 absence or inhibition by PMX53, with possible association to neuroprotective effects [355]. PMX53 efficacy in these models set the possibility of being effective for drug-resistant seizures types. The limitation of PMX53 is its short half-life [355]; therefore, new brain-permeable C5ar1 inhibitors with an improved pharmacokinetic profile need to be developed.
The complement receptor C5ar1 expression on microglia has been reported upregulated following kainate-induced seizures, which is controlled by the Fosb gene, a mediator of transcriptional factor, activator protein-1 (AP-1) [356]. Therefore, under excitotoxic conditions, Fosb gene products contribute to microglial activation in the brain through regulation of microglial C5ar1 expression [356].
Additionally, classical complement pathway markers (C1q and iC3b) were altered alongside the phagocytic signaling molecules (Trem2 and Pros1) in human brain samples obtained from patients with focal cortical dysplasia [357], suggesting that aberrant phagocytic signaling and complement activation occurs in human drug-resistant epilepsy [357]. The alteration of phagocytic pathways may contribute to unwanted elimination of cells/synapses and/or impaired clearance of dead cells, whereas the classical complement pathway may be a candidate mechanism contributing to epileptogenic remodeling of the synaptic circuitry associated with human drug-resistant epilepsy [357]. In epileptic animals, SE induced a long-lasting increase in C1q, C3 and iC3b proteins in the hippocampus that correlated with higher seizure frequency [358]. However, how the hyperactivation of the classical complement pathway directly contributes to the molecular/neuronal and/or clinical pathology of SE and TLE remains unknown.
Complement factors may also serve as biomarkers for the epilepsy diagnosis since increased serum levels of these proteins have been found in epileptic patients [359]. The serum level of C3 complement protein was found to be higher in untreated epileptic patients than in healthy controls or treated epileptic patients, suggesting complement involvement in seizures generation [359]. Recently, changes were identified in the plasma concentration of a panel of complement analytes (including markers of classical, alternative and terminal activation pathways) between patients with epilepsy and controls, controlled and uncontrolled epilepsy and with certain AEDs [360].
The first successful therapeutic treatment to inhibit the complement system consists of targeting the terminal pathway with the use of an anti-C5 antibody, named eculizumab [361]. Eculizumab (Soliris™, Alexion Pharmaceuticals) has proven safe and effective in managing paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) [361,362,363]. Eculizumab treatment blocks the cleavage of C5 and prevents the formation of the MAC but leaves the rest of the complement system intact [361]. Although eculizumab and many other complement inhibitors have not been tested in epilepsy, there are questions about the safety of chronic inhibition of complement components and which key proteins to block in all complement pathways, since the complement system is an important part of the immune system.
These data add further evidence to the role of complement dysregulation that could mediate relevant changes related to seizure generation and to the pathogenesis of epilepsy or drug-resistant epilepsy.

9. Transient Receptor Potential Vanilloid Type 1 (TRPV1)

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated nonselective cation channel and member of the vanilloid TRP family. In the chromosome 17p13 is located the Trpv1 gene, which encodes a 95-kDa protein containing 839 amino acid residues [364]. TRPV1 has six transmembrane domains (TM), presenting a pore region located between TM5 and TM6 domains. The N-terminal tail allows binding of calmodulin and ATP to modulate TRPV1 activation while C-terminus contains a TRP domain and binding sites for phosphatidylinositol 4,5-bisphosphate (PIP2) and calmodulin [364].
TRPV1 is a nonselective cation channel with permeability to calcium (Ca2+), protons (low pH) [365], polyvalent cations, anandamide and arachidonic acid metabolites [366,367].
When these channels are stimulated, they increase permeability to Na+ and Ca2+, therefore increasing neuronal excitability [368,369]. Furthermore, they respond to stimuli such as noxious heat [368], oxidative stress and vanilloids (i.e., capsaicin, olvanil and resiniferatoxin) [368]. In addition, the mitochondrial activation of TRPV1 induces an increase of Ca2+ concentration, mitochondrial reactive oxygen species production and MAPK activation, which correlates with an augmented migration of microglia [370].
TRPV1 was first reported in sensory neurons of the dorsal root ganglion, nodose ganglia and trigeminal ganglia [364]. In the brain, it is found in regions of the hypothalamus, cerebellum, cerebral cortex, striatum, midbrain, hippocampus and substantia nigra [371]. The human hippocampus and cortex express relatively high levels of TRPV1 mRNA [371]. On the other side, the subcellular localization of TRPV1 is in the inhibitory and excitatory synapses of the dentate molecular layer (ML), in the postsynaptic dendritic membranes in the mouse hippocampus [372,373]. Moreover, they are expressed in nonneuronal cells such as epidermal keratinocytes [374], urinary bladder epithelial cells [375], pancreatic islet beta cells [376], neutrophil granulocytes [377], human brain endothelium [378] and human peripheral blood [379].
Current knowledge demonstrates that activation of TRPV1 mediates synaptic plasticity, facilitating long-term potentiation and suppressing long-term depression [380], neurotransmitter release [381,382,383] and the enhancement of synaptic excitation [384]. TRPV1 activation regulates spontaneous glutamate release in an activity-dependent manner in rodent brain [382,385] and human cortical tissue [369].
Additionally, in recent years, extensive research has been directed towards studying TRPV1, because it is also involved in the pathophysiology of diseases such as schizophrenia [386], stroke [387], pain [388], depression [389], anxiety [390], Parkinson’s disease [391] and epilepsy [392].

TRPV1 and Epilepsy

Because TRPV1 regulates neuronal excitability, this channel could be a promising therapeutic target for the treatment of epilepsy. For this reason, we provide a brief description of the TRPV1 effects in preclinical and clinical models of epilepsy.
In TRPV1 knockout mice, there was an observed reduction in the susceptibility to hyperthermic seizures, as well as a delay in seizure latency, short seizure duration and a decrease in seizure severity compared to wild type mice [393], suggesting that the reduction of TRPV1 expression paralleled a decreased susceptibility to febrile seizures. Furthermore, TRPV1 knockout mice showed a decrease in susceptibility to generalized clonic-seizures induced by PTZ [394].
In vitro studies showed that capsazepine (CPZ, a TRPV1 antagonist) suppressed the epileptiform activity induced by 4-aminopyridine (4-AP) in mice hippocampal slices. In contrast, capsaicin (a TRPV1 agonist) promoted epileptiform activity [395]. These results support a role for TRPV1 in the suppression of epileptiform activity, indicating that antagonism of TRPV1 could be a target for effective acute suppression of seizures [395].
Other studies have also reported the antiepileptic actions of the TRPV1 antagonists. Regarding genetically epilepsy-prone rats (GEPR-3s), CPZ (a TRPV1 antagonist) reduced seizure severity in a dose-dependent manner in male rats and in female rats CPZ suppressed seizure susceptibility [396]. With the application of CPZ and other TRPV1 antagonists such as 5-iodoresiniferatoxin and α-Spinasterol, seizures were suppressed, regardless of the method of induction (4-AP, PTZ, maximal electroshock test, 6 Hz stimulation) [392,395,397,398,399,400]. CPZ also decreased intracellular reactive oxygen species production, mitochondrial membrane depolarization, apoptosis and the levels of caspases 3 and 9, in the hippocampus and dorsal root ganglion of rats in the 4-AP model [392,400] where inhibition of TRPV1 activity can result in neuroprotective effects in the epileptic neurons.
On the other side, it has been reported an increased expression of protein and mRNA levels of TRPV1 in the hippocampus, mainly in CA1 and CA3 areas, during acute and chronic phases of pilocarpine-induced SE [401,402].
Regarding TRPV1 agonists, capsaicin enhanced spontaneous excitatory postsynaptic currents (EPSC) frequency and TRPV1 protein expression in the dentate gyrus of mice with TLE [384]. N-oleoyldopamine (a TRPV1 agonist), increased the incidence and duration of generalized clonic-tonic seizures as well as decreased the latency of myoclonic seizures, both in the PTZ- and amygdala-kindling models [403]. However, AMG-9810 (a TRPV1 antagonist), reduced not only the duration of generalized clonic-tonic seizures in the PTZ-kindling model but also the duration of afterdischarges in the amygdala-kindling model [403].
Patients with mesial TLE showed upregulation of mRNA and protein expression levels of TRPV1 in the temporal cortex and hippocampus [404]. TRPV1 were mainly distributed in the cell bodies and dendrites of neurons and in astrocytes and co-localized with glutamatergic and GABAergic neurons [404], suggesting that the overexpression and distribution patterns of TRPV1 might be involved in the pathogenesis and epileptogenesis of human TLE [404].
Taken together, these findings support the role of TRPV1 in the etiology of epilepsy. Systemic administration of TRPV1 antagonists seems to be a novel therapeutic target for epilepsy, given their antiepileptic, antiepileptogenic or neuroprotective effects in preclinical models.
The effectiveness of TRPV1 antagonists should be studied with caution, as there are no chronic studies that show pharmacokinetic profile, efficacy and tolerability in preclinical models of epilepsy. Furthermore, there are currently no clinical trials with TRPV1 antagonists demonstrating its effectiveness in epileptic patients.
In the future, it will be interesting to investigate the TRPV1 involvement in drug-resistant epilepsy, in both preclinical models and surgically resected human tissue, where these studies may lead to knowing whether TRPV1 participates in the pathophysiology of drug-resistant epilepsy and if they could be a new therapeutic target.

10. Galanin and Galanin Receptors

Galanin is a 30 amino acid residue long endogenous neuropeptide that presents an N-terminal core fragment formed by residues of Gly1, Trp2, Asn5, Tyr9 and Gly12 and is associated with maintaining high affinity with galanin-receptors [405].
Galanin is widely distributed in both the peripheral and CNS of several mammalian species [406]. In the CNS, it is an inducible neuropeptide which concentration can be increased (2–10-fold) by physiological regulators such as estrogen [407], vasoactive intestinal peptide [408], thyroid hormone [409], progesterone [410], nerve growth factor [411] and brain-derived nerve growth factor [412].
Galanin can be co-expressed with neurotransmitters such as acetylcholine, serotonin, glutamate, GABA, noradrenalin and dopamine [413], as well as with neuropeptides such as encephalin, neuropeptide Y, substance P, vasopressin, calcitonin gene-regulated peptide and gonadotropin-releasing hormone [414].
Galanin participates in biological processes such as feeding [415], nociception [416], nerve regeneration [417], arousal/sleep regulation [418], sexual behavior [419], learning [420], memory [421], neuroendocrine release [422] and gut secretion and contractility [423].
In addition, it is involved in pathological processes such as ischemic brain damage [424], chronic stress [425], nerve injury [426], multiple sclerosis [427] and Alzheimer’s disease [428].
Galanin actions are mediated through three G-protein-coupled receptors, namely GalR1, GalR2 and GalR3, which are linked to different signaling cascades [429]. These galanin-receptors have extensive distribution throughout the CNS, mainly in the hippocampus, hypothalamus, locus coeruleus neurons and medulla oblongata [430,431].
The GalR1 contains 349 amino acids and it is located on chromosome 18q23 [432]. The activation of GalR1 induces the hyperpolarization of the presynaptic terminals by opening ATP-dependent K+ channels, thus inhibiting glutamate release in the hippocampus [433,434]. Additionally, GalR1 has been shown to directly close voltage-gated Ca2+ channels which could also hyperpolarize the presynaptic membrane and prevent glutamate release [435]. GalR1 has also been involved in the regulation of the transcription factors cAMP response element-binding protein (CREB) and the immediate early gene c-fos, in specific brain regions [436,437].
The GalR1 and GalR3 receptors act via a Gαi/o-protein, resulting in the activation of G protein-regulated inwardly rectifying K+ channels, as well as in a decrease of adenylate cyclase (AC) activity and cytosolic cAMP levels [438,439,440].
The GalR2 is conformed by 387 amino acids and located on the chromosome 17q25.3 [441]. GalR2 signals through several classes of G-proteins, the most common being the stimulation of the phospholipase C via Gαq/11-protein family, which increases inositol phosphate hydrolysis, mediating the release of Ca2+ into the cytoplasm from intracellular stores and opening Ca2+-dependent chloride channels [441]. GalR2 activation via Gαi/o-protein induces the regulation of CREB in mouse dentate gyrus [436] as well as the stimulation of MAPK/ERK1/2 pathway in different cell types [439,442,443,444].
GalR3 contains 368 amino acids and it is located on chromosome 22q12.2–13.1 [445]. The role of GalR3 in the brain is less studied. However, the evidence suggest that GalR3 activation increases neural stem cells viability [446]. GalR3 activation also affects the phosphorylation of CREB [447] and has a more restricted expression to hypothalamus and areas of the mid- and hindbrain, as compared with the other galanin-receptors [448].
In general, the galaninergic innervation is abundant in the hippocampus, and it has been suggested that this peptide modulates the activity of principal neuronal populations in the dentate gyrus and CA3-CA1 through the activity of GalR1 and GalR2 [449].

Galanin and Galanin-Receptors in Epilepsy

Galanin is a modulator of classical neurotransmitters and is present in brain areas intimately involved in epilepsy, which makes galanin an interesting therapeutic target to study in relation to its involvement in the generation and spread of seizures, with the end goal of developing novel approaches for the treatment of epilepsy.
In this context, a depletion of galanin immunoreactivity has been reported in nerve fibers of all hippocampal areas after SE, induced by stimulation of the perforant path-pathway [450]. However, in the SE induced by KA, it was demonstrated that galanin was significantly upregulated after SE. These changes were transient, most often limited to 6–24-h post-seizure and returning to baseline by 72 h [451]. On the other hand, galanin induced a dose-dependent antiepileptic effect in the picrotoxin-kindling model when administered into the lateral brain ventricle, hippocampus, caudate nuclei, substantia nigra reticulata and nucleus accumbens [452].
In vitro studies with human hippocampal slices obtained from patients with TLE, showed that galanin applied directly to slices had no significant effect in stimulation-induced EPSPs (excitatory postsynaptic potentials) in dentate gyrus and CA1. Autoradiographic binding revealed the presence of galanin-receptors and the functional receptor binding assay showed impaired functionality of these receptors, suggesting that the signaling pathways could be altered [453]. In addition, in TLE patients, a pathogenic missense mutation in the galanin gene has been identified [454].
All previous results suggest that alterations in galanin-receptor binding and downstream signaling could have a role in the generation of seizures [454].
It has been found that GalR1 mediates galanin protection from seizures and seizure-induced hippocampal injury in models of limbic SE. GalR1 knockout mice present severe seizures, profound injury in the CA1 pyramidal cell layer, as well as injury to hilar interneurons and dentate granule cells, in Li-pilocarpine and electrical perforant path stimulation (PPS) models [455]. These mice also presented spontaneous seizures ranging from facial movements to SE [456], which is probably associated with changes in the distribution and expression levels of several neuropeptides in some principal hippocampal neurons, such as a strong upregulation of galanin expression only in neurons in the polymorph layer of the dentate gyrus [457]. However, GalR2 knockout mice showed no change in seizure latency or the number of animals with seizures versus wild type mice, in PTZ and flurothyl models [458]. In the electrical PPS model, GalR2 knockout mice showed neuronal damage in the dentate hilus, hilar injury and increase of seizure severity [459].
GalR1-/-mice (mice with an insertional inactivating mutation within the gene encoding GalR1) showed more susceptibility to tonic-clonic seizures in response to bright overhead lighting or handling [456], and developed spontaneous seizures of partial onset with secondary generalization [460]. The above indicates a critical role for GalR1 in the regulation of the antiseizure activity of galanin.
Different GalRs agonists and positive allosteric modulators have shown anticonvulsive and antiepileptogenic effects in different animal models. For example, M617 (a GalR1 agonist) administered during 24 h by intrahippocampal infusion in wistar rats, increased the after-discharge threshold and delayed the onset of seizures, but did not block the occurrence of generalized seizures, in the rapid kindling model [461]. These results suggest that the activation of GalR1 decreased the excitability of the hippocampus and delayed, although it did not prevent, the epileptogenesis induced by the kindling. On the other hand, galanin(1-29) (a GalR1/2 agonist) and galanin(2-11) (a GalR2 agonist) completely prevented the occurrence of full kindled seizures [461], where both agonists could have an antiepileptogenic effect possibly mediated by GalR2. However, galmic (a nonpeptide galanin-receptor agonist) had a dose dependent effect, decreasing seizures and reducing the severity and duration of spikes of SE induced for the perforant path stimulation in the hippocampus of mice [462].
The galanin analogs (Gal-(K) 4, Gal-B5, Gal-B6, and Gal-B7) showed some protection against seizures in the 6 Hz corneal stimulation model. However, only Gal-B2 (NAX-5055) provides 100% protection against seizures in the same model [463], and in the Frings audiogenic seizure susceptible mouse model [464]. Furthermore, NAX-5055 reduced the vesicular release of glutamate and increased the extracellular level of GABA in cerebellar, neocortical and hippocampal slices of rats [465], which partly explains the anticonvulsant effect of NAX-5055 observed in epilepsy models [465].
The GalR1 agonist, galnon, seems to reduce the severity and increased the latency of PTZ-induced seizures [466]. While its intrahippocampal injection shortened the duration of self-sustaining SE induced by perforant path stimulation [466]. NAX 810-2, a GalR2 agonist, blocked in a dose-dependent manner seizures induced by corneal kindling and 6 Hz stimulation [467]. Although CYM2503 (a GalR2-positive allosteric modulator) did not seem to block the establishment of SE, it increased the latency to seizure and to SE, and, more importantly, it appeared to decrease mortality dramatically, in the Li-pilocarpine model [468]. CYM2503 also attenuated electroshock-induced seizures [468].
Another line of evidence that suggests an antiseizure effect due to galanin is the overexpression of galanin in animal models of epilepsy.
Overexpression of galanin in dentate granule cells and hippocampal and cortical pyramidal neurons delays seizure generalization during hippocampal kindling [469]. Galanin overexpressed ectopically (GalOE) in the olfactory bulb of mouse modulated high frequency excitatory synaptic transmission, increased latency to behavioral convulsions and increased the number of stimulations necessary to reach the fully kindled state [470]. This finding suggests that galanin overexpressed outside of the hippocampal formation has a significant effect, which could contribute to inhibiting seizures in the brain [470]. Furthermore, overexpression of the galanin through viral vectors suppressed generalized seizures in kindled rats [471]. Adeno-associated virus (AAV)-mediated expression and constitutive secretion of galanin, prevented neuronal cell death and blocked limbic seizure activity induced by KA and kindling [472,473,474], demonstrating an antiseizure effectiveness of galanin.
The evidence shown suggests that galanin and galanin-receptors represent promising novel targets for drug development for the treatment of epilepsy. However, galanin and galanin-receptors agonists have low bioavailability due to rapid degradation by peptidases, low permeability through the BBB, and time to peak effect of 30 min; they are biologically unstable, with a half-life less than 1.2 h; and there are currently no agonists and antagonists with a high level of specificity. Only NAX 5055 (with high affinity for GalR1-GalR2) was found to be biologically active after intravenous, intraperitoneal and subcutaneous administration, and its efficacy was associated with a linear pharmacokinetic profile [464]. For this reason, the employment of AAV vectors for expression and constitutive secretion of galanin is an important tool for the development of antiepileptic gene therapy. The study of galanin and galanin-receptors in epilepsy should be focused on promoting the search for new therapeutic targets as well as the development of new drugs such as peptidomimetics of galanin, non-peptide agonists or positive allosteric modulators. Finally, it would be interesting to investigate their potential use as therapeutic targets in drug-resistant epilepsy.

11. Melatonin and Melatonin-Receptors

Melatonin (N-acetyl-5-methoxytryptamine, an indoleamine derivative of serotonin) is a neurohormone synthesized and secreted during the night by the pineal gland [475]. Tryptophan first converts to serotonin, and then melatonin synthesis takes place via a two-step pathway: the first step is catalyzed by arylalkylamine N-acetyltransferase enzyme to N-acetylserotonin and the cycle ends with the synthesis of melatonin by enzyme hydroxyindole-O-methyltransferase [476].
The melatonin secretion pattern is regulated by the suprachiasmatic nucleus of the hypothalamus [477]. Melatonin is also produced by other organs such as the retina [478], skin [479], gastrointestinal tract [480], bone marrow [481] and lymphocytes [482].
Melatonin regulates several mammalian biological processes such as circadian rhythm [483], sleep [484], reproduction [485], retinal physiology [478], glucose homeostasis [486], memory [487], blood pressure control [488], immune function [489] and free-radical scavenging [490]. Furthermore, other results suggest that melatonin has antinociceptive [491], antidepressant [492], antioxidant [493] and anxiolytic effects [494].
Melatonin acts on a receptor family composed of MT1, MT2 and MT3. The melatonin-receptors have been localized in areas of the nervous system and peripheral tissues of both rodents and humans [495]. Their distribution in the brain includes the cerebellum, occipital cortex, parietal cortex, temporal cortex, thalamus, frontal cortex, striatum, substantia nigra, ventral tegmental area, nucleus accumbens, caudate-putamen, hippocampus and suprachiasmatic nucleus [495].
The MT1 receptor contains 350 amino acid residues and is located in the chromosome 4q35.1 [496]. The MT1 receptor couples to Gαi/o protein which leads to the inhibition of cAMP formation, protein kinase A (PKA) activity and phosphorylation of CREB [497]. In addition, MT1 receptor couples to Gq/11 protein increasing phosphatidylinositol turnover and intracellular calcium [497]. MT1 receptors can also increase the phosphorylation of the MAPK/ERK1/2 pathway, as well as potassium conductance through Kir inwardly rectifying channels [498].
The MT2 receptor contains 362 amino acids residues and is located in the chromosome 11q21-q22 [499]. Similar to the MT1 receptor, the MT2 receptor is coupled to Gαi/o proteins inhibiting both forskolin-stimulated cAMP production and cGMP formation, activating protein kinase C (PKC) and decreasing calcium-dependent dopamine release in the retina [500].
The MT3 receptor has been characterized as a quinone reductase 2 enzyme (QR2, EC 1.10.99.2). The QR2-enzyme participates in the protection against oxidative stress by preventing electron transfer reactions of quinones [501].
Additionally, melatonin also exerts an effect on other targets, such as inhibiting the NMDA receptor in rat striatum [502], and enhancing central GABAergic transmission by modulating GABA receptor activity in the rat brain [503]. Other evidence suggests that melatonin may inhibit calcium influx resulting in inhibition of neuronal nitric oxide synthase (nNOS) activity, a decrease of NO production and an excitatory effect over NMDA receptors in the rat brain [504]. Besides, melatonin induces increases the affinity of the D2 receptors in the rat striatum [505]. All of this evidence suggests that melatonin could be a potent drug candidate for various neurological diseases such as epilepsy.

Melatonin and Melatonin Receptors in Epilepsy

Melatonin is widely used for sleep disorders [506]. Besides, melatonin has antioxidant properties and is able to reduce neuronal excitability and protect the brain [493]. Based on these characteristics, different studies have started to assess a possible antiseizure effect by melatonin. However, the role of melatonin as an anticonvulsant hormone is due to the fact that it easily passes the BBB [507].
Much of the available literature points out to the anticonvulsant effects of melatonin in animal models. In vitro studies showed that melatonin depresses low-Mg2+ epileptiform neuronal activity through specific neocortical receptors, on human temporal neocortical slices [508]. In vivo, melatonin significantly raised the electroconvulsive threshold test in mice [509]; increased the after-discharge threshold and suppressed generalized seizures in the amygdala kindling model [510]; and increased the latency to epileptiform activity and decreased the frequency of spike and spike-wave activity, on penicillin-induced epileptiform activity in rats [511].
In addition, melatonin showed anticonvulsant effects when it was administered prior to the induction of hyperthermic febrile seizures in rats [512]. The subchronic treatment with melatonin increased the latency of pilocarpine-induced convulsions in rats and the number of [3H] GABA binding sites in hippocampal slices [513]. This suggests that melatonin actions might be due to positive modulation of GABAergic transmission [513]. Melatonin pretreatment before PTZ administration lowered the mortality rate, attenuated seizure severity and increased seizure latency in guinea pigs [514].
Pinealectomy (pineal gland removal), seemed to accelerate the amygdala kindling process by reducing the number of stimulations needed to reach fully kindled stage [515], suggesting that endogenous melatonin may act as a neuroprotective factor, as it was observed at pinealectomized epileptic rats, after SE induction in the pilocarpine model [516].
Although melatonin cotreatment did not significantly alter seizure activity, it improved the survival rate, attenuated KA-induced microglial activation and lipid peroxidation associated with hippocampal neurodegeneration, in melatonin cotreated rats [517,518]. In addition, melatonin increased the latency in the appearance of spontaneous recurrent seizures and decreased their frequency, while the hippocampal neuronal damage was reduced, in the KA-induced SE model [519]. However, long-term melatonin treatment after SE was unable to suppress the development of epileptogenesis [519]. These findings suggest that melatonin exerts a neuroprotective action against KA-induced excitotoxicity resulting from its role as a free radical scavenger, antioxidant, antiapoptotic or anti-inflammatory agent [517,518,519].
In the pilocarpine-induced SE model, animals treated with melatonin just before, during or after SE, exhibited an increased latency to SE, a survival rate of 100% after SE, a decreased number of seizures in the chronic period and hippocampal neuronal preservation [520]. Moreover, long-term melatonin administration after SE, reduced neuronal loss showing a region-specific pattern of neuronal protection along the rostro-caudal axis of the dorsal hippocampus [521]. These results confirm an important role for melatonin in the epileptogenic process as well as the control of seizures.
In relation to the mRNA expression levels of MT1 and MT2, they were increased in the rat hippocampus a few hours after pilocarpine-induced SE [522], but, during the silent phase, MT1 returned to normal levels while MT2 level was reduced [522]. This study suggests that pilocarpine-induced SE could modify melatonin-receptor proteins and mRNA expression levels in the hippocampus of rats.
With respect to melatoninergic ligands, the use of ramelteon (a MT1/MT2 agonist) showed anticonvulsant properties in the rapid kindling model, supporting melatonin-receptors as potential novel targets for anticonvulsant drug development [523]. VLB-01 (beprodone, a MT3/QR2 agonist), demonstrated an anticonvulsant profile in several animal models such as the MES test, PTZ, pilocarpine-induced seizures and PTZ-kindled model [524]. Additionally, VLB-01 has been tested in phase I and II clinical trials for the treatment of refractory focal seizures and focal onset seizures secondarily generalized, where it had a reduction on seizure frequency after 224 days, in comparison to placebo [524]. On the other hand, agomelatine (a MT1/MT2 agonist and 5HT2C antagonist) had an anticonvulsant and neuroprotective action in chronic post-SE treatment [525].
Regarding human studies, it has been observed that in children with febrile seizures, there is a lower concentration of melatonin in both saliva and plasma [526,527]. Moreover, the plasma melatonin level showed an increase during seizures but a significantly lower level post-seizure [527]. Regarding patients with TLE, they showed low melatonin baseline levels, which increased following seizures [528]. In children with intractable epilepsy, diurnal melatonin plasma levels were decreased [529]. After children received oral melatonin for three months, 87% of patients reported an improvement in seizure frequency and seizure severity [529], a result that supports the use of melatonin in patients with intractable seizures and low melatonin levels given its anticonvulsant effect. In children with severe uncontrolled epilepsy (infantile spasms and Lennox–Gastaut syndrome) that were treated with melatonin plus AEDs for three months, a decrease in seizure frequency was reported [530].
Melatonin has shown to be an adjunctive treatment in the case of severe infantile myoclonic epilepsy [531]. Gupta et al. [532,533] investigated the effect of add-on melatonin on the blood levels of antioxidant enzymes (glutathione peroxidase and glutathione reductase), in epileptic children on valproate or carbamazepine monotherapy. They found an increase in the antioxidant activity of both enzymes, suggesting that melatonin exerts antioxidant activity in these patients [532,533]. Therefore, melatonin, as an adjunct, could exert a neuroprotective effect due to its antioxidant, antiexcitotoxic and free radical scavenging properties within the CNS.
However, oral administration of melatonin increases seizures in four out of five neurologically disabled young people with generalized tonic-clonic epilepsy [534]. Besides, the single case report of a 21-year-old woman with uncontrolled epilepsy under melatonin treatment, showed an increase in the epileptiform activity [535]. This evidence shows that melatonin promotes or worsens seizures in some epileptic patients.
Other authors reported that melatonin did not exacerbate seizures in epileptic children [536,537], but it was effective in treating sleep disorders [537]. However, a study in patients with severe epilepsy showed variable results as 27% of patients had an increased seizure rate, 63% of patients had a decrease and 10% of patients had no observable differences [538].
Melatonin can act as an anticonvulsant, an antioxidant and a neuroprotector in epilepsy. Melatonin and melatoninergic ligands may be suitable for use as add-on treatments with common AEDs. However, some studies suggest that melatonin worsens seizures or does not improve seizures in patients with epilepsy. Therefore, it is necessary to continue investigating how melatonin and melatonin-receptors act during the epileptogenesis process not only in preclinical models of epilepsy but also in drug-resistant epilepsy models.

12. Other Potential Therapeutic Targets to Consider

Some other therapeutic targets that have come to our attention are mentioned below, which might have a potential use in controlling epilepsy and drug-resistant epilepsy in the future.

12.1. G protein-Coupled Receptors

Other therapeutic targets are the G protein-coupled receptors (GPCRs), also known as the seven-transmembrane (7-TM) receptors, that comprise the largest super protein family of receptors that detect extracellular molecules and trigger signal transmission inside of the cell [539]. GPCRs might play some essential roles in the mediation of neuronal excitability via regulating Gαs and Gαi-controlled cAMP signaling, as well as Gαq-initiated Ca2+-sensitive pathways [539].
In this context, they have emerged as candidates for epileptogenic mediators owing to their essential roles in the regulation of ion channel functions, thereby altering neuronal excitability and setting the seizure threshold [539]. These receptors include prostanoid receptors, cannabinoid receptors, adenosine receptors, histamine receptors and metabotropic glutamate receptors (mGluRs). Understanding their role in seizure generation and development of epilepsy could help to develop new antiepileptic or antiepileptogenic drugs.
Among the prostanoid receptor subtypes, EP1, EP2 and FP are the most studied in acute seizures and epilepsy models [539,540,541,542,543,544,545,546,547,548,549,550,551,552]. The pharmacological inhibition or the genetic inactivation of the EP1 receptor demonstrated its contribution to increasing neuronal excitability and lowering the seizure threshold [540,542,543,548]. On the other hand, previous studies suggested that systemic pharmacologic inhibition of the EP2 receptor reduced brain inflammation and injury following pilocarpine-induced seizures in mice [545,546]. Later, it was demonstrated that pharmacological inhibition of the EP2 receptor (with TG4-155/TG6-10-1 antagonists) affords a broad spectrum of anti-inflammatory and neuroprotective effects in several rodent models of SE [547,553]. These findings support the notion of the EP2 receptor as an emerging target for adjunctive treatment, together with the current first-line anticonvulsants and glutamate receptor blockers, to prevent acute brain inflammation and damage following SE [547,553].
Concerning the endocannabinoid system, it consists of two currently known GPCRs: cannabinoid receptor type 1 (CB1) and type 2 (CB2) [554]. In contrast to the CB1 receptor that is generally considered as one of the most abundant GPCRs in the CNS, the CB2 receptor in normal conditions has very limited distribution in the brain [555,556]. Activation/inhibition of the cannabinoid receptors can modulate a wide range of intracellular and intercellular signaling activity, such as ion channels (i.e., potassium, sodium, and calcium channels), intracellular calcium ion concentrations, and inflammation [557]. In this way, CB1 and CB2 receptors can reduce neuronal activity and excitability of the brain, thereby generating interest and directing efforts into modulating these two inhibitory GPCRs as potential therapies for seizures or epilepsy [539,558,559]. It appears that the majority of studies about the CB1 receptor in various in vitro and in vivo models indicate that CB1 receptor activation causes anticonvulsant effects, while inhibiting CB1 receptors might aggravate convulsive seizures [560,561,562,563,564].
Since the CB2 receptor can be expressed by activated brain microglia, this receptor has emerged as an appealing anti-inflammatory target for brain conditions. Recently, one study suggests that targeting the CB2 receptor with the selective inverse agonist SMM-189, might represent an adjunctive therapeutic strategy for reducing brain inflammation and damage following prolonged seizures, together with first-line anticonvulsant agents and glutamate receptor blockers [565].
In relation to endocannabinoid receptors and drug-resistant epilepsy, a study revealed reduced mRNA and protein expression levels of CB1 receptors in the hippocampus of patients with drug-resistant TLE, especially in glutamatergic axon terminals [566]. Recently, it was demonstrated that drug-resistant mesial TLE is associated with a higher CB1 receptor-induced Gi/o protein activation level, as well as an increased tissue content of specific endocannabinoids in the hippocampus and the temporal neocortex [567].
However, although cannabinoids show promise as an anticonvulsant and anti-inflammatory treatment, their promiscuous binding affinity for numerous receptors makes the task of identifying their beneficial and detrimental mechanisms of action challenging [559].

12.2. BDNF/TrkB Signaling

Neurotrophin brain-derived neurotrophic factor (BDNF) is the most widely studied neurotrophin in the mammalian nervous system [568]. Via its tropomyosin-related kinase receptor B (TrkB), this neurotrophin regulates a variety of physiological processes such as learning, memory and reward [568,569]. BDNF/TrkB signaling is thought to play a critical role in epilepsy [570,571].
BDNF expression increases following epileptic seizures in experimental animals and patients with TLE [572,573,574,575]. Intracerebroventricular infusion of antibodies that recognize TrkB blocked the kindling development in rats [576]. On the other hand, the increased TrkB signaling is related to seizure induction in a mouse kindling model [577,578].
The fact that the downstream effector phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) seems essential to BDNF/TrkB-mediated epileptogenesis in the kindling model [579] also points to BDNF/TrkB/PLCγ1 signaling as a possible molecular mechanism by which SE induces TLE [580,581] providing a new therapeutic target for possible epilepsy prevention.
Recent findings suggest that COX-2 via PGE2/EP2 signaling regulates the hippocampal BDNF/TrkB pathway following prolonged seizures. Thus, EP2 inhibition by brain-permeable antagonists such as TG6-10-1 might provide a novel strategy to suppress the abnormal TrkB activity, an event that can trigger epileptogenesis and consequently generate epilepsy [582].
Taken together, these studies provide evidence of the contribution of BDNF/TrkB signaling to epileptogenesis, the process by which a normal brain becomes epileptic. By selectively disrupting pathways downstream or upstream it could be possible to regulate BDNF/TrkB signaling, which would hopefully result in the treatment not only of epilepsy but also of drug-resistant epilepsy, where the use of matrix encapsulated cell lines secreting human BDNF provides an interesting option for patients with drug-resistant TLE [583].

12.3. Pannexins

Pannexins, a family of membrane proteins, are nonselective, large-pore channels mediating extracellular exchange of neuroactive molecules [584,585,586]. Three proteins coded by pannexin genes have been identified: pannexin-1 and pannexin-2 are abundantly found in the central nervous system (CNS), while pannexin-3 is not [587]. In the CNS, pannexin-1 channels are expressed in both neurons and astroglia [587,588,589,590]; they mediate the release of adenosine 5′-triphosphate (ATP) and the excitatory neurotransmitter glutamate [591]; and they have a vital role in modulating cellular hyperexcitability [584,585,586].
Recent data suggest that these channels are activated under pathological conditions such as epilepsy and regulate neuronal excitability [586,592,593,594,595]. Pannexin-1 expression seems raised in animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy [586,596,597,598,599]. Recently, it was reported that pannexin-1 channel activation promotes seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors [600]. Genetic or pharmacological targeting of pannexin-1 channels have anticonvulsant effects in epilepsy models [595,600]. These results suggest that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating not only epilepsy but also drug-resistant epilepsy.

13. Conclusions and Future Perspectives

For the development of new treatment tools, it is necessary to continue exploring key targets associated with the progression of chronic epilepsy. We provide an overview of promising research directions in drug therapy not only for seizures or epilepsy but also for drug-resistant epilepsy.
Starting with molecular pathways such as mTOR and Wnt/β-catenin pathways, which are often disrupted following seizures and in chronic epilepsy, they could be considered as favorable antiepileptogenic targets for future drug therapies, as their inhibition has beneficial effects as protecting against neuronal damage and death. With respect to zinc supplementation as a therapeutic strategy, it is necessary to continue investigating this line of research, as there exist different sources of zinc and because it modulates a variety of ion channels and receptors, resulting in pro- or anticonvulsant effects besides neuronal neurotoxicity.
On the other hand, carbonic anhydrase inhibitors have shown anticonvulsant effects, but it is still necessary to identify and evaluate new specific inhibitors such as carbonic anhydrase-VII inhibitors, as anticonvulsant or antiepileptogenic drugs. For erythropoietin and erythropoietin-derived mimetic peptides, it has been reported they have neuroprotective or anti-inflammatory effects. Copine 6 (neuronal-copine) expression is significantly increased in the epileptic brain where it seems to be involved in controlling different signaling pathways and synaptic plasticity. However, only recently has it begun to be elucidated its role in epilepsy. The complement system (complex innate immune system) seems to contribute to seizures as well as neurodegeneration after its excessive activation. Thus, inhibition of key complement proteins might avoid seizure generation and epileptogenesis process. The inhibition of C5a complement receptor 1 (C5ar1) or the use of an anti-C5 antibody (eculizumab) has not yet been tested in epilepsy or drug-resistant epilepsy, but both targets are promising as epileptic therapeutics tools.
Antagonism of TRPV1 channels, peptidomimetics, non-peptide agonists or positive allosteric modulators of galanin, have also displayed anticonvulsant, antiepileptogenic and neuroprotective actions. Melatonin and melatoninergic ligands may exert neuroprotective effects due to its antioxidant, antiexcitotoxic and free radical scavenging properties besides their anticonvulsant effects, suggesting their application as an adjunct therapy.
All these evidences expose promising therapeutic approaches for the development of pharmacological therapies to control epileptic seizures, to prevent the onset and progression of chronic epilepsy, and in their potential use in drug-resistant epilepsy as well. However, further research is still necessary to evaluate how these therapeutic interventions can be applied safely without causing undesirable side effects, especially in combination with already commonly prescribed AEDs, with the end goal of translating preclinical and clinical findings and research to the development of new and safe therapeutic drugs.
Finally, another point worth considering and researching is the simultaneous modulation of two or more of these key therapeutic approaches as a promising avenue to prevent the development of chronic epilepsy and drug-resistant epilepsy, without losing sight of the broader possible effects on other functions mediated by these therapeutic targets, including those that are critical for the regulation of many physiological functions and normal cellular processes.

Author Contributions

Conceptualization, C.Z.-T.; Writing—Original Draft Preparation, C.Z.-T., M.C.-H. and H.L.-M.; and Writing—Review and Editing, C.Z.-T., M.C.-H. and H.L.-M. All authors have read and agreed to the published version of the manuscript.

Funding

H.L.-M. is partially funded by UNAM-DGAPA-PAPIIT (project IA200719).

Acknowledgments

We thank A.I. Gutierrez-Lerma for English review and improvement.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

TLEtemporal lobe epilepsy
AEDsantiepileptic drugs
KAkainic acid
SEstatus epilepticus
PTZPentylenetetrazole
BBBblood–brain barrier
CNScentral nervous system

References

  1. Devinsky, O.; Vezzani, A.; O’Brien, T.J.; Jette, N.; Scheffer, I.E.; De Curtis, M.; Perucca, P. Epilepsy. Nat. Rev. Dis. Prim. 2018, 4, 18024. [Google Scholar] [CrossRef]
  2. Kalilani, L.; Sun, X.; Pelgrims, B.; Noack-Rink, M.; Villanueva, V. The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis. Epilepsia 2018, 59, 2179–2193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Kwan, P.; Arzimanoglou, A.; Berg, A.T.; Brodie, M.J.; Hauser, W.A.; Mathern, G.; Moshé, S.L.; Perucca, E.; Wiebe, S.; French, J. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2009, 51, 1069–1077. [Google Scholar] [CrossRef] [PubMed]
  4. Engel, J. Mesial Temporal Lobe Epilepsy: What Have We Learned? Neuroscientist 2001, 7, 340–352. [Google Scholar] [CrossRef] [PubMed]
  5. Kwan, P. The natural history of epilepsy: An epidemiological view. J. Neurol. Neurosurg. Psychiatry 2004, 75, 1376–1381. [Google Scholar] [CrossRef] [PubMed]
  6. Löscher, W. Strategies for antiepileptogenesis: Antiepileptic drugs versus novel approaches evaluated in post-status epilepticus models of temporal lobe epilepsy. In Jasper’s Basic Mechanisms of the Epilepsies, 4th ed.; Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., Delgado-Escueta, A.V., Eds.; National Center for Biotechnology Information: Bethesda, MD, USA, 2012. [Google Scholar]
  7. Pitkänen, A.; Lukasiuk, K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011, 10, 173–186. [Google Scholar] [CrossRef]
  8. Nusse, R.; Brown, A.; Papkoff, J.; Scambler, P.; Shackleford, G.; McMahon, A.; Moon, R.; Varmus, H. A new nomenclature for int-1 and related genes: The Wnt gene family. Cell 1991, 64, 231. [Google Scholar] [CrossRef]
  9. Nusse, R.; Varmus, H. Three decades of Wnts: A personal perspective on how a scientific field developed. EMBO J. 2012, 31, 2670–2684. [Google Scholar] [CrossRef] [Green Version]
  10. MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell. 2009, 17, 9–26. [Google Scholar] [CrossRef] [Green Version]
  11. Van Amerongen, R.; Nusse, R. Towards an integrated view of Wnt signaling in development. Development 2009, 136, 3205–3214. [Google Scholar] [CrossRef] [Green Version]
  12. Buechling, T.; Boutros, M. Wnt Signaling. Curr. Top. Dev. Biol. 2011, 97, 21–53. [Google Scholar] [CrossRef]
  13. Axelrod, J.D. Progress and challenges in understanding planar cell polarity signaling. Semin. Cell Dev. Biol. 2009, 20, 964–971. [Google Scholar] [CrossRef] [PubMed]
  14. Wu, J.; Mlodzik, M. A quest for the mechanism regulating global planar cell polarity of tissues. Trends Cell Biol. 2009, 19, 295–305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Kühl, M.; Sheldahl, L.C.; Park, M.; Miller, J.R.; Moon, R.T. The Wnt/Ca2+ pathway. Trends Genet. 2000, 16, 279–283. [Google Scholar] [CrossRef]
  16. Kohn, A.D.; Moon, R.T. Wnt and calcium signaling: β-Catenin-independent pathways. Cell Calcium 2005, 38, 439–446. [Google Scholar] [CrossRef]
  17. Aberle, H.; Bauer, A.; Stappert, J.; Kispert, A.; Kemler, R. β-catenin is a target for the ubiquitin–proteasome pathway. EMBO J. 1997, 16, 3797–3804. [Google Scholar] [CrossRef] [Green Version]
  18. Liu, C.; Li, Y.; Semenov, M.; Han, C.; Baeg, G.-H.; Tan, Y.; Zhang, Z.; Lin, X.; He, X. Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism. Cell 2002, 108, 837–847. [Google Scholar] [CrossRef] [Green Version]
  19. Stamos, J.L.; Weis, W.I. The -Catenin Destruction Complex. Cold Spring Harb. Perspect. Biol. 2012, 5, a007898. [Google Scholar] [CrossRef]
  20. Bilic, J.; Huang, Y.-L.; Davidson, G.; Zimmermann, T.; Cruciat, C.-M.; Bienz, M.; Niehrs, C. Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation. Science 2007, 316, 1619–1622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Mikels, A.J.; Nusse, R. Wnts as ligands: Processing, secretion and reception. Oncogene 2006, 25, 7461–7468. [Google Scholar] [CrossRef] [Green Version]
  22. Arrázola, M.S.; Varela-Nallar, L.; Colombres, M.; Toledo, E.M.; Cruzat, F.; Pavez, L.; Assar, R.; Aravena, A.; Gonzalez, M.; Montecino, M.; et al. Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/β-catenin signaling pathway. J. Cell. Physiol. 2009, 221, 658–667. [Google Scholar] [CrossRef] [PubMed]
  23. Hödar, C.; Assar, R.; Colombres, M.; Aravena, A.; Pavez, L.; González, M.; Martínez, S.; Inestrosa, N.C.; Maass, A. Genome-wide identification of new Wnt/β-catenin target genes in the human genome using CART method. BMC Genom. 2010, 11, 348. [Google Scholar] [CrossRef] [PubMed]
  24. Lie, D.C.; Colamarino, S.A.; Song, H.-J.; Désiré, L.; Mira, H.; Consiglio, A.; Lein, E.S.; Jessberger, S.; Lansford, H.; Dearie, A.R.; et al. Wnt signalling regulates adult hippocampal neurogenesis. Nat. Cell Biol. 2005, 437, 1370–1375. [Google Scholar] [CrossRef] [PubMed]
  25. Madsen, T.M.; Newton, S.S.; Eaton, M.E.; Russell, D.S.; Duman, R.S. Chronic electroconvulsive seizure up-regulates β-catenin expression in rat hippocampus: Role in adult neurogenesis. Biol. Psychiatry 2003, 54, 1006–1014. [Google Scholar] [CrossRef]
  26. Rubio, A.R.-A.C. Increase Signaling of Wnt/β-Catenin Pathway and Presence of Apoptosis in Cerebellum of Kindled Rats. CNS Neurol. Disord. Drug Targets 2017, 16, 1. [Google Scholar] [CrossRef]
  27. Theilhaber, J.; Rakhade, S.N.; Sudhalter, J.; Kothari, N.; Klein, P.; Pollard, J.; Jensen, F.E. Gene Expression Profiling of a Hypoxic Seizure Model of Epilepsy Suggests a Role for mTOR and Wnt Signaling in Epileptogenesis. PLoS ONE 2013, 8, e74428. [Google Scholar] [CrossRef] [PubMed]
  28. Yang, J.; Zhang, X.; Wu, Y.; Zhao, B.; Liu, X.; Pan, Y.; Liu, Y.; Ding, Y.; Qiu, M.; Wang, Y.-Z.; et al. Wnt/β-catenin signaling mediates the seizure-facilitating effect of postischemic reactive astrocytes after pentylenetetrazole-kindling. Glia 2016, 64, 1083–1091. [Google Scholar] [CrossRef]
  29. Qu, Z.; Su, F.; Qi, X.; Sun, J.; Wang, H.; Qiao, Z.; Zhao, H.; Zhu, Y. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy. Cell Biochem. Funct. 2017, 35, 472–476. [Google Scholar] [CrossRef]
  30. Campos, V.E.; Du, M.; Li, Y. Increased seizure susceptibility and cortical malformation in β-catenin mutant mice. Biochem. Biophys. Res. Commun. 2004, 320, 606–614. [Google Scholar] [CrossRef]
  31. Gorter, J.A.; Iyer, A.M.; White, I.; Colzi, A.; Van Vliet, E.A.; Sisodiya, S.M.; Aronica, E. Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol. Dis. 2014, 62, 508–520. [Google Scholar] [CrossRef]
  32. Pirone, A.; Alexander, J.; Lau, L.A.; Hampton, D.; Zayachkivsky, A.; Yee, A.; Yee, A.; Jacob, M.H.; Dulla, C.G. APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures. Neurobiol. Dis. 2017, 98, 149–157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Paciorkowski, A.R.; Thio, L.L.; Dobyns, W.B. Genetic and Biologic Classification of Infantile Spasms. Pediatr. Neurol. 2011, 45, 355–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Yu, X.; Malenka, R.C. β-catenin is critical for dendritic morphogenesis. Nat. Neurosci. 2003, 6, 1169–1177. [Google Scholar] [CrossRef] [PubMed]
  35. Ehenríquez, J.P.; Salinas, P.C. Dual roles for Wnt signalling during the formation of the vertebrate neuromuscular junction. Acta Physiol. 2011, 204, 128–136. [Google Scholar] [CrossRef] [PubMed]
  36. Xu, W.; Kimelman, D. Mechanistic insights from structural studies of beta-catenin and its binding partners. J. Cell Sci. 2007, 120, 3337–3344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Fortress, A.M.; Frick, K.M. Hippocampal Wnt Signaling. Neuroscientist 2016, 22, 278–294. [Google Scholar] [CrossRef]
  38. Busceti, C.L.; Biagioni, F.; Aronica, E.; Riozzi, B.; Storto, M.; Battaglia, G.; Giorgi, F.S.; Gradini, R.; Fornai, F.; Caricasole, A.; et al. Induction of the Wnt Inhibitor, Dickkopf-1, Is Associated with Neurodegeneration Related to Temporal Lobe Epilepsy. Epilepsia 2007, 48, 694–705. [Google Scholar] [CrossRef]
  39. Zorn, A.M. Wnt signalling: Antagonistic Dickkopfs. Curr. Biol. 2001, 11, R592–R595. [Google Scholar] [CrossRef] [Green Version]
  40. Grotewold, L. The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death. EMBO J. 2002, 21, 966–975. [Google Scholar] [CrossRef] [Green Version]
  41. Grotewold, L.; Rüther, U. Bmp, Fgf and Wnt signalling in programmed cell death and chondrogenesis during vertebrate limb development: The role of Dickkopf-1. Int. J. Dev. Biol. 2002, 46, 943–947. [Google Scholar]
  42. Caricasole, A.; Copani, A.; Caruso, A.; Caraci, F.; Iacovelli, L.; Sortino, M.A.; Terstappen, G.C.; Nicoletti, F. The Wnt pathway, cell-cycle activation and β-amyloid: Novel therapeutic strategies in Alzheimer’s disease? Trends Pharmacol. Sci. 2003, 24, 233–238. [Google Scholar] [CrossRef]
  43. Willert, K.; Nusse, R. β-catenin: A key mediator of Wnt signaling. Curr. Opin. Genet. Dev. 1998, 8, 95–102. [Google Scholar] [CrossRef]
  44. Klein, P.S.; Melton, D.A. A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA 1996, 93, 8455–8459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Chae, W.-J.; Ehrlich, A.K.; Chan, P.Y.; Teixeira, A.M.; Henegariu, O.; Hao, L.; Shin, J.H.; Park, J.-H.; Tang, W.H.; Kim, S.-T.; et al. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 2016, 44, 246–258. [Google Scholar] [CrossRef] [Green Version]
  46. Scott, E.L.; Brann, D.W. Estrogen regulation of Dkk1 and Wnt/β-Catenin signaling in neurodegenerative disease. Brain Res. 2012, 1514, 63–74. [Google Scholar] [CrossRef] [Green Version]
  47. Coghlan, M.P.; A Culbert, A.; Cross, D.A.; Corcoran, S.L.; Yates, J.W.; Pearce, N.J.; Rausch, O.L.; Murphy, G.J.; Carter, P.S.; Cox, L.R.; et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 2000, 7, 793–803. [Google Scholar] [CrossRef] [Green Version]
  48. Lange, C.; Mix, E.; Frahm, J.; Glass, Ä.; Müller, J.; Schmitt, O.; Schmöle, A.-C.; Klemm, K.; Ortinau, S.; Hübner, R.; et al. Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells. Neurosci. Lett. 2011, 488, 36–40. [Google Scholar] [CrossRef]
  49. Atkinson, J.M.; Rank, K.B.; Zeng, Y.; Capen, A.; Yadav, V.; Manro, J.R.; Engler, T.A.; Chedid, M. Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma—Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS ONE 2015, 10, e0125028. [Google Scholar] [CrossRef] [Green Version]
  50. Morales-Garcia, J.A.; Luna-Medina, R.; Alonso-Gil, S.; Sanz-SanCristobal, M.; Palomo, V.; Gil, C.; Santos, A.; Martinez, A.; Perez-Castillo, A. Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo. ACS Chem. Neurosci. 2012, 3, 963–971. [Google Scholar] [CrossRef] [Green Version]
  51. Licht-Murava, A.; Paz, R.; Vaks, L.; Avrahami, L.; Plotkin, B.; Eisenstein, M.; Eldar-Finkelman, H. A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci. Signal. 2016, 9, ra110. [Google Scholar] [CrossRef]
  52. Laplante, M.; Sabatini, D.M. mTOR Signaling. Cold Spring Harb. Perspect. Biol. 2011, 4, a011593. [Google Scholar] [CrossRef] [PubMed]
  53. Laplante, M.; Sabatini, D.M. mTOR Signaling in Growth Control and Disease. Cell 2012, 149, 274–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Crino, P.B. The mTOR signalling cascade: Paving new roads to cure neurological disease. Nat. Rev. Neurol. 2016, 12, 379–392. [Google Scholar] [CrossRef] [PubMed]
  55. Switon, K.; Kotulska, K.; Janusz-Kaminska, A.; Zmorzynska, J.; Jaworski, J. Molecular neurobiology of mTOR. Neuroscientist 2017, 341, 112–153. [Google Scholar] [CrossRef] [Green Version]
  56. Wullschleger, S.; Loewith, R.J.; Hall, M.N. TOR Signaling in Growth and Metabolism. Cell 2006, 124, 471–484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Powell, J.D.; Delgoffe, G.M. The Mammalian Target of Rapamycin: Linking T Cell Differentiation, Function, and Metabolism. Immunity 2010, 33, 301–311. [Google Scholar] [CrossRef] [Green Version]
  58. Jacinto, E.; Loewith, R.; Schmidt, A.; Lin, S.; Rüegg, M.A.; Hall, A.; Hall, M.N. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 2004, 6, 1122–1128. [Google Scholar] [CrossRef]
  59. Huang, K.; Fingar, D.C. Growing knowledge of the mTOR signaling network. Semin. Cell Dev. Biol. 2014, 36, 79–90. [Google Scholar] [CrossRef] [Green Version]
  60. Baybis, M.; Yu, J.; Lee, A.; Golden, J.A.; Weiner, H.; McKhann, G.; Aronica, E.; Crino, P.B. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol. 2004, 56, 478–487. [Google Scholar] [CrossRef]
  61. Holz, M.K. The role of S6K1 in ER-positive breast cancer. Cell Cycle 2012, 11, 3159–3165. [Google Scholar] [CrossRef] [Green Version]
  62. Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science 2005, 307, 1098–1101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Cross, D.A.E.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nat. Cell Biol. 1995, 378, 785–789. [Google Scholar] [CrossRef] [PubMed]
  64. Brunet, A.; Bonni, A.; Zigmond, M.J.; Lin, M.Z.; Juo, P.; Hu, L.S.; Anderson, M.J.; Arden, K.C.; Blenis, J.; Greenberg, M.E. Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor. Cell 1999, 96, 857–868. [Google Scholar] [CrossRef] [Green Version]
  65. Lozovaya, N.A.; Gataullina, S.; Tsintsadze, T.; Pallesipocachard, E.; Minlebaev, M.; Goriounova, N.A.; Buhler, E.M.; Watrin, F.; Shityakov, S.; Becker, A.J.; et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat. Commun. 2014, 5, 4563. [Google Scholar] [CrossRef] [PubMed]
  66. Tarkowski, B.; Kuchcinska, K.; Blazejczyk, M.; Jaworski, J.; Bartosz, T.; Kinga, K.; Magdalena, B.; Jacek, J. Pathological mTOR mutations impact cortical development. Hum. Mol. Genet. 2019, 28, 2107–2119. [Google Scholar] [CrossRef] [PubMed]
  67. Ma, X.M.; Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 2009, 10, 307–318. [Google Scholar] [CrossRef]
  68. Ran, I.; Gkogkas, C.G.; Vasuta, C.; Tartas, M.; Khoutorsky, A.; Laplante, I.; Parsyan, A.; Nevarko, T.; Sonenberg, N.; Lacaille, J.-C. Selective Regulation of GluA Subunit Synthesis and AMPA Receptor-Mediated Synaptic Function and Plasticity by the Translation Repressor 4E-BP2 in Hippocampal Pyramidal Cells. J. Neurosci. 2013, 33, 1872–1886. [Google Scholar] [CrossRef] [Green Version]
  69. Kumar, V.; Zhang, M.-X.; Swank, M.W.; Kunz, J.; Wu, G.-Y. Regulation of Dendritic Morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK Signaling Pathways. J. Neurosci. 2005, 25, 11288–11299. [Google Scholar] [CrossRef] [Green Version]
  70. Han, J.; Wang, B.; Xiao, Z.; Gao, Y.; Zhao, Y.; Zhang, J.; Chen, B.; Wang, X.; Dai, J. Mammalian target of rapamycin (mTOR) is involved in the neuronal differentiation of neural progenitors induced by insulin. Mol. Cell. Neurosci. 2008, 39, 118–124. [Google Scholar] [CrossRef]
  71. Fishwick, K.J.; Li, R.A.; Halley, P.; Deng, P.; Storey, K.G. Initiation of neuronal differentiation requires PI3-kinase/TOR signalling in the vertebrate neural tube. Dev. Biol. 2010, 338, 215–225. [Google Scholar] [CrossRef] [Green Version]
  72. Garza-Lombó, C.; Schroder, A.; Reyes-Reyes, E.M.; Franco, R. mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Curr. Opin. Toxicol. 2018, 8, 102–110. [Google Scholar] [CrossRef]
  73. Pernet, V.; Schwab, M.E. Lost in the jungle: New hurdles for optic nerve axon regeneration. Trends Neurosci. 2014, 37, 381–387. [Google Scholar] [CrossRef] [PubMed]
  74. Figlia, G.; Gerber, D.; Suter, U. Myelination and mTOR. Glia 2018, 66, 693–707. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Russo, C.D.; Lisi, L.; Feinstein, U.L.; Navarra, P. mTOR kinase, a key player in the regulation of glial functions: Relevance for the therapy of multiple sclerosis. Glia 2012, 61, 301–311. [Google Scholar] [CrossRef] [PubMed]
  76. Lee, C.-C.; Huang, C.-C.; Hsu, K.-S. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 2011, 61, 867–879. [Google Scholar] [CrossRef] [PubMed]
  77. Raab-Graham, K.F.; Haddick, P.C.G.; Jan, Y.N.; Jan, L.Y. Activity- and mTOR-Dependent Suppression of Kv1.1 Channel mRNA Translation in Dendrites. Science 2006, 314, 144–148. [Google Scholar] [CrossRef]
  78. Wang, Y.; Barbaro, M.F.; Baraban, S.C. A role for the mTOR pathway in surface expression of AMPA receptors. Neurosci. Lett. 2006, 401, 35–39. [Google Scholar] [CrossRef]
  79. Jaworski, J.; Sheng, M. The Growing Role of mTOR in Neuronal Development and Plasticity. Mol. Neurobiol. 2006, 34, 205–220. [Google Scholar] [CrossRef]
  80. Stoica, L.; Zhu, P.J.; Huang, W.; Zhou, H.; Kozma, S.C.; Costa-Mattioli, M. Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc. Natl. Acad. Sci. USA 2011, 108, 3791–3796. [Google Scholar] [CrossRef] [Green Version]
  81. Huang, W.; Zhu, P.J.; Zhang, S.; Zhou, H.; Stoica, L.; Galiano, M.; Krnjević, K.; Roman, G.; Costa-Mattioli, M. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat. Neurosci. 2013, 16, 441–448. [Google Scholar] [CrossRef] [Green Version]
  82. Malik, A.R.; Urbanska, M.; Macias, M.; Skalecka, A.; Jaworski, J. Beyond control of protein translation: What we have learned about the non-canonical regulation and function of mammalian target of rapamycin (mTOR). Biochim. Biophys. Acta 2013, 1834, 1434–1448. [Google Scholar] [CrossRef] [PubMed]
  83. Lipton, J.O.; Sahin, M. The Neurology of mTOR. Neuron 2014, 84, 275–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Cleary, C.; Linde, J.; Hiscock, K.; Hadas, I.; Belmaker, R.; Agam, G.; Flaisher-Grinberg, S.; Einat, H. Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders. Brain Res. Bull. 2008, 76, 469–473. [Google Scholar] [CrossRef] [PubMed]
  85. Jernigan, C.S.; Goswami, D.B.; Austin, M.C.; Iyo, A.H.; Chandran, A.; Stockmeier, C.A.; Karolewicz, B. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2011, 35, 1774–1779. [Google Scholar] [CrossRef] [Green Version]
  86. Siuta, M.A.; Robertson, S.D.; Kocalis, H.; Saunders, C.; Gresch, P.J.; Khatri, V.; Shiota, C.; Kennedy, J.P.; Lindsley, C.W.; Daws, L.C.; et al. Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice. PLoS Biol. 2010, 8, e1000393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Howell, K.R.; Law, A.J. Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development. Schizophr. Res. 2020, 217, 95–104. [Google Scholar] [CrossRef]
  88. Steinmetz, A.B.; Stern, S.A.; Kohtz, A.S.; Descalzi, G.; Alberini, C.M. Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice. J. Neurosci. 2018, 38, 1015–1029. [Google Scholar] [CrossRef]
  89. Rosina, E.; Battan, B.; Siracusano, M.; Di Criscio, L.; Hollis, F.; Pacini, L.; Curatolo, P.; Bagni, C. Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Transl. Psychiatry 2019, 9, 1–10. [Google Scholar] [CrossRef]
  90. Spencer, B.; Potkar, R.; Trejo, M.; Rockenstein, E.; Patrick, C.; Gindi, R.; Adame, A.; Wyss-Coray, T.; Masliah, E. Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in -Synuclein Models of Parkinson’s and Lewy Body Diseases. J. Neurosci. 2009, 29, 13578–13588. [Google Scholar] [CrossRef] [Green Version]
  91. Lan, A.-P.; Chen, J.; Zhao, Y.; Chai, Z.; Hu, Y. mTOR Signaling in Parkinson’s Disease. NeuroMol. Med. 2017, 19, 1–10. [Google Scholar] [CrossRef]
  92. Spilman, P.; Podlutskaya, N.; Hart, M.J.; Debnath, J.; Gorostiza, O.; Bredesen, D.; Richardson, A.; Strong, R.; Galvan, V. Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease. PLoS ONE 2010, 5, e9979. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Citraro, R.; Leo, A.; Constanti, A.; Russo, E.; De Sarro, G. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol. Res. 2016, 107, 333–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Hodges, S.L.; Lugo, J.N. Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy. Epilepsy Res. 2020, 161, 106282. [Google Scholar] [CrossRef] [PubMed]
  95. Miyata, H.; Chiang, A.C.Y.; Vinters, H.V. Insulin signaling pathways in cortical dysplasia and TSC-tubers: Tissue microarray analysis. Ann. Neurol. 2004, 56, 510–519. [Google Scholar] [CrossRef] [PubMed]
  96. Chu-Shore, C.J.; Major, P.; Camposano, S.; Muzykewicz, D.; Thiele, E.A. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2009, 51, 1236–1241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Blümcke, I.; Spreafico, R.; Haaker, G.; Coras, R.; Kobow, K.; Bien, C.G.; Pfäfflin, M.; Elger, C.; Widman, G.; Schramm, J.; et al. Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery. N. Engl. J. Med. 2017, 377, 1648–1656. [Google Scholar] [CrossRef] [Green Version]
  98. Wong, M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia 2010, 51, 27–36. [Google Scholar] [CrossRef] [Green Version]
  99. Sadowski, K.; Kotulska-Jóźwiak, K.; Jóźwiak, S. Role of mTOR inhibitors in epilepsy treatment. Pharmacol. Rep. 2015, 67, 636–646. [Google Scholar] [CrossRef]
  100. Zeng, L.-H.; Xu, L.; Gutmann, D.H.; Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 2008, 63, 444–453. [Google Scholar] [CrossRef] [Green Version]
  101. Buckmaster, P.S.; Ingram, E.A.; Wen, X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J. Neurosci. 2009, 29, 8259–8269. [Google Scholar] [CrossRef] [Green Version]
  102. Zeng, L.-H.; Rensing, N.R.; Wong, M. The Mammalian Target of Rapamycin Signaling Pathway Mediates Epileptogenesis in a Model of Temporal Lobe Epilepsy. J. Neurosci. 2009, 29, 6964–6972. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Macias, M.; Blazejczyk, M.; Kazmierska, P.; Caban, B.; Skalecka, A.; Tarkowski, B.; Rodo, A.; Konopacki, J.; Jaworski, J. Spatiotemporal Characterization of mTOR Kinase Activity Following Kainic Acid Induced Status Epilepticus and Analysis of Rat Brain Response to Chronic Rapamycin Treatment. PLoS ONE 2013, 8, e64455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Shima, A.; Nitta, N.; Suzuki, F.; Laharie, A.-M.; Nozaki, K.; Depaulis, A. Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio-temporal lobe epilepsy. Eur. J. Neurosci. 2015, 41, 976–988. [Google Scholar] [CrossRef] [PubMed]
  105. Zhang, B.; Wong, M. Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia 2012, 53, 506–511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Van Vliet, E.A.; Forte, G.; Holtman, L.; Burger, J.C.G.D.; Sinjewel, A.; De Vries, H.E.; Aronica, E.; Gorter, J.A. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia 2012, 53, 1254–1263. [Google Scholar] [CrossRef] [PubMed]
  107. Kim, Y.S.; Choi, M.Y.; Lee, N.H.; Jeon, B.T.; Roh, G.S.; Kim, H.J.; Kang, S.S.; Cho, G.J.; Choi, W.S. Decreased interaction between FoxO3a and Akt correlates with seizure-induced neuronal death. Epilepsy Res. 2014, 108, 367–378. [Google Scholar] [CrossRef]
  108. Bhowmik, M.; Khanam, R.; Saini, N.; Vohora, D. Activation of AKT/GSK3β pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice. Neuro Toxicol. 2015, 46, 44–52. [Google Scholar] [CrossRef]
  109. Talos, D.M.; Bs, L.M.J.; Gourmaud, S.; Ba, C.A.C.; Sun, H.; Lim, K.-C.; Lucas, T.H.; Davis, K.A.; Martinez-Lage, M.; Jensen, F.E. Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy. Ann. Neurol. 2018, 83, 311–327. [Google Scholar] [CrossRef]
  110. Goto, E.M.; Silva, M.D.P.; Perosa, S.R.; Argañaraz, G.A.; Pesquero, J.B.; Cavalheiro, É.A.; Naffah-Mazzacoratti, M.G.; Teixeira, V.P.C.; Silva, J.A. Akt pathway activation and increased neuropeptide Y mRNA expression in the rat hippocampus: Implications for seizure blockade. Neuropeptides 2010, 44, 169–176. [Google Scholar] [CrossRef]
  111. Brewster, A.L.; Lugo, J.N.; Patil, V.V.; Lee, W.L.; Qian, Y.; Vanegas, F.; Anderson, A.E. Rapamycin Reverses Status Epilepticus-Induced Memory Deficits and Dendritic Damage. PLoS ONE 2013, 8, e57808. [Google Scholar] [CrossRef]
  112. McDaniel, S.S.; Wong, M. Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci. Lett. 2011, 497, 231–239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Buckmaster, P.S.; Lew, F. Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J. Neurosci. 2011, 31, 2337–2347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Huang, X.; McMahon, J.; Yang, J.; Shin, D.; Huang, Y. Rapamycin down-regulates KCC2 expression and increases seizure susceptibility to convulsants in immature rats. Neuroscience 2012, 219, 33–47. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Hartman, A.L.; Santos, P.; Dolce, A.; Hardwick, J.M. The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice. PLoS ONE 2012, 7, e45156. [Google Scholar] [CrossRef] [Green Version]
  116. Heng, K.; Haney, M.M.; Buckmaster, P.S. High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 2013, 54, 1535–1541. [Google Scholar] [CrossRef]
  117. Sliwa, A.; Plucinska, G.; Bednarczyk, J.; Lukasiuk, K. Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci. Lett. 2012, 509, 105–109. [Google Scholar] [CrossRef]
  118. Muncy, J.; Butler, I.J.; Koenig, M.K. Rapamycin reduces seizure frequency in tuberous sclerosis complex. J. Child Neurol. 2009, 24, 477. [Google Scholar] [CrossRef] [Green Version]
  119. Krueger, D.A.; Care, M.M.; Holland, K.; Agricola, K.; Tudor, C.; Mangeshkar, P.; Wilson, K.A.; Byars, A.; Sahmoud, T.; Franz, D.N. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. New Engl. J. Med. 2010, 363, 1801–1811. [Google Scholar] [CrossRef]
  120. Krueger, D.A.; Wilfong, A.A.; Holland-Bouley, K.; Anderson, A.E.; Agricola, K.; Tudor, C.; Mays, M.; Lopez, C.M.; Kim, M.-O.; Franz, D.N. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann. Neurol. 2013, 74, 679–687. [Google Scholar] [CrossRef]
  121. Perek-Polnik, M.; Jóźwiak, S.; Jurkiewicz, E.; Perek, D.; Kotulska-Jóźwiak, K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 2012, 16, 83–85. [Google Scholar] [CrossRef]
  122. Cardamone, M.; Flanagan, D.; Mowat, D.; Kennedy, S.E.; Chopra, M.; Lawson, J.A. Mammalian Target of Rapamycin Inhibitors for Intractable Epilepsy and Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex. J. Pediatr. 2014, 164, 1195–1200. [Google Scholar] [CrossRef] [PubMed]
  123. Meikle, L.; Pollizzi, K.; Egnor, A.; Kramvis, I.; A Lane, H.; Sahin, M.; Kwiatkowski, D.J. Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function. J. Neurosci. 2008, 28, 5422–5432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Klawitter, J.; Nashan, B.; Christians, U. Everolimus and sirolimus in transplantation-related but different. Expert Opin. Drug Saf. 2015, 14, 1055–1070. [Google Scholar] [CrossRef] [PubMed]
  125. Brandt, C.; Hillmann, P.; Noack, A.; Römermann, K.; Öhler, L.A.; Rageot, D.; Beaufils, F.; Melone, A.; Sele, A.M.; Wymann, M.P.; et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology 2018, 140, 107–120. [Google Scholar] [CrossRef]
  126. Rageot, D.; Bohnacker, T.; Melone, A.; Langlois, J.-B.; Borsari, C.; Hillmann, P.; Sele, A.M.; Beaufils, F.; Zvelebil, M.; Hebeisen, P.; et al. Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders. J. Med. Chem. 2018, 61, 10084–10105. [Google Scholar] [CrossRef]
  127. Rageot, D.; Bohnacker, T.; Keles, E.; McPhail, J.A.; Hoffmann, R.M.; Melone, A.; Borsari, C.; SriRamaratnam, R.; Sele, A.M.; Beaufils, F.; et al. (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase. J. Med. Chem. 2019, 62, 6241–6261. [Google Scholar] [CrossRef] [Green Version]
  128. Gericke, B.; Brandt, C.; Theilmann, W.; Welzel, L.; Schidlitzki, A.; Twele, F.; Kaczmarek, E.; Anjum, M.; Hillmann, P.; Löscher, W. Selective inhibition of mTORC1/2 or PI3K/mTORC1/2 signaling does not prevent or modify epilepsy in the intrahippocampal kainate mouse model. Neuropharmacology 2020, 162, 107817. [Google Scholar] [CrossRef]
  129. Coleman, J.E. Zinc Proteins: Enzymes, Storage Proteins, Transcription Factors, and Replication Proteins. Annu. Rev. Biochem. 1992, 61, 897–946. [Google Scholar] [CrossRef]
  130. Takeda, A. Movement of zinc and its functional significance in the brain. Brain Res. Rev. 2000, 34, 137–148. [Google Scholar] [CrossRef]
  131. Klug, A. The Discovery of Zinc Fingers and Their Applications in Gene Regulation and Genome Manipulation. Annu. Rev. Biochem. 2010, 79, 213–231. [Google Scholar] [CrossRef] [Green Version]
  132. Kambe, T.; Tsuji, T.; Hashimoto, A.; Itsumura, N. The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 2015, 95, 749–784. [Google Scholar] [CrossRef] [PubMed]
  133. Maret, W. Zinc in Cellular Regulation: The Nature and Significance of “Zinc Signals” . Int. J. Mol. Sci. 2017, 18, 2285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Huang, L.; Tepaamorndech, S. The SLC30 family of zinc transporters – A review of current understanding of their biological and pathophysiological roles. Mol. Asp. Med. 2013, 34, 548–560. [Google Scholar] [CrossRef] [PubMed]
  135. Wenzel, H.J.; Cole, T.B.; Born, D.E.; Schwartzkroin, P.A.; Palmiter, R.D. Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc. Natl. Acad. Sci. USA 1997, 94, 12676–12681. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Palmiter, R.D.; Cole, T.B.; Quaife, C.J.; Findley, S.D. ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc. Natl. Acad. Sci. USA 1996, 93, 14934–14939. [Google Scholar] [CrossRef] [Green Version]
  137. Palmiter, R.; Findley, S. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J. 1995, 14, 639–649. [Google Scholar] [CrossRef]
  138. Palmiter, R.D. Protection against zinc toxicity by metallothionein and zinc transporter 1. Proc. Natl. Acad. Sci. USA 2004, 101, 4918–4923. [Google Scholar] [CrossRef] [Green Version]
  139. Sekler, I.; Moran, A.; Hershfinkel, M.; Dori, A.; Margulis, A.; Birenzweig, N.; Nitzan, Y.; Silverman, W.F. Distribution of the zinc transporter ZnT-1 in comparison with chelatable zinc in the mouse brain. J. Comp. Neurol. 2002, 447, 201–209. [Google Scholar] [CrossRef]
  140. Rafalo-Ulinska, A.; Piotrowska, J.; Kryczyk, A.; Opoka, W.; Sowa-Kucma, M.; Misztak, P.; Rajkowska, G.; Stockmeier, C.A.; Datka, W.; Nowak, G.; et al. Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims. J. Psychiatr. Res. 2016, 83, 220–229. [Google Scholar] [CrossRef] [Green Version]
  141. Rafalo, A.; Zadrozna, M.; Nowak, B.; Kotarska, K.; Wiatrowska, K.; Pochwat, B.; Sowa-Kucma, M.; Misztak, P.; Nowak, G.; Szewczyk, B. The level of the zinc homeostasis regulating proteins in the brain of rats subjected to olfactory bulbectomy model of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2017, 72, 36–48. [Google Scholar] [CrossRef]
  142. Cousins, R.J.; Liuzzi, J.P.; Lichten, L.A. Mammalian Zinc Transport, Trafficking, and Signals. J. Biol. Chem. 2006, 281, 24085–24089. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Liuzzi, J.P.; Cousins, R.J. Mammalian zinc transporters. Annu. Rev. Nutr. 2004, 24, 151–172. [Google Scholar] [CrossRef] [PubMed]
  144. Schweigel-Röntgen, M. The Families of Zinc (SLC30 and SLC39) and Copper (SLC31) Transporters. Co-Transp. Syst. 2014, 73, 321–355. [Google Scholar] [CrossRef]
  145. Krężel, A.; Hao, Q.; Maret, W. The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch. Biochem. Biophys. 2007, 463, 188–200. [Google Scholar] [CrossRef] [PubMed]
  146. Masters, B.A.; Quaife, C.J.; Erickson, J.C.; Kelly, E.J.; Froelick, G.J.; Zambrowicz, B.P.; Brinster, R.L.; Palmiter, R.D. Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J. Neurosci. 1994, 14, 5844–5857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Choi, D.; Yokoyama, M.; Koh, J. Zinc neurotoxicity in cortical cell culture. Neuroscience 1988, 24, 67–79. [Google Scholar] [CrossRef]
  148. Perry, D.K.; Smyth, M.J.; Stennicke, H.R.; Salvesen, G.S.; Duriez, P.J.; Poirier, G.G.; Hannun, Y.A. Zinc Is a Potent Inhibitor of the Apoptotic Protease, Caspase-3. J. Biol. Chem. 1997, 272, 18530–18533. [Google Scholar] [CrossRef] [Green Version]
  149. Côté, A.; Chiasson, M.; Peralta, M.R.; LaFortune, K.; Pellegrini, L.; Tóth, K. Cell type-specific action of seizure-induced intracellular zinc accumulation in the rat hippocampus. J. Physiol. 2005, 566, 821–837. [Google Scholar] [CrossRef]
  150. Plum, L.M.; Rink, L.; Haase, H. The Essential Toxin: Impact of Zinc on Human Health. Int. J. Environ. Res. Public Health 2010, 7, 1342–1365. [Google Scholar] [CrossRef] [Green Version]
  151. Hosie, A.M.; Dunne, E.L.; Harvey, R.J.; Smart, T.G. Zinc-mediated inhibition of GABAA receptors: Discrete binding sites underlie subtype specificity. Nat. Neurosci. 2003, 6, 362–369. [Google Scholar] [CrossRef]
  152. Paoletti, P.; Vergnano, A.; Barbour, B.; Casado, M. Zinc at glutamatergic synapses. Neuroscience 2009, 158, 126–136. [Google Scholar] [CrossRef] [PubMed]
  153. Sensi, S.L.; Paoletti, P.; Bush, A.I.; Sekler, I. Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci. 2009, 10, 780–791. [Google Scholar] [CrossRef] [PubMed]
  154. Assaf, S.Y.; Chung, S.-H. Release of endogenous Zn2+ from brain tissue during activity. Nat. Cell Biol. 1984, 308, 734–736. [Google Scholar] [CrossRef] [PubMed]
  155. Qian, J.; Noebels, J.L. Visualization of transmitter release with zinc fluorescence detection at the mouse hippocampal mossy fibre synapse. J. Physiol. 2005, 566, 747–758. [Google Scholar] [CrossRef]
  156. Frederickson, C.J.; Suh, S.W.; Silva, D.; Frederickson, C.J.; Thompson, R.B. Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron. J. Nutr. 2000, 130, 1471S–1483S. [Google Scholar] [CrossRef]
  157. Kay, A.R.; Toth, K. Is Zinc a Neuromodulator? Sci. Signal. 2008, 1, re3. [Google Scholar] [CrossRef]
  158. Sensi, S.L.; Paoletti, P.; Koh, J.-Y.; Aizenman, E.; Bush, A.I.; Hershfinkel, M. The Neurophysiology and Pathology of Brain Zinc. J. Neurosci. 2011, 31, 16076–16085. [Google Scholar] [CrossRef]
  159. Frederickson, C.J.; Koh, J.-Y.; Bush, A.I. The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 2005, 6, 449–462. [Google Scholar] [CrossRef]
  160. Tóth, K. Zinc in Neurotransmission. Annu. Rev. Nutr. 2011, 31, 139–153. [Google Scholar] [CrossRef]
  161. Marger, L.; Schubert, C.; Bertrand, D. Zinc: An underappreciated modulatory factor of brain function. Biochem. Pharmacol. 2014, 91, 426–435. [Google Scholar] [CrossRef]
  162. Noh, S.; Lee, S.R.; Jeong, Y.J.; Ko, K.S.; Rhee, B.D.; Kim, N.; Han, J. The direct modulatory activity of zinc toward ion channels. Integr. Med. Res. 2015, 4, 142–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Besser, L.; Chorin, E.; Sekler, I.; Silverman, W.F.; Atkin, S.; Russell, J.T.; Hershfinkel, M. Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus. J. Neurosci. 2009, 29, 2890–2901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Chorin, E.; Vinograd, O.; Fleidervish, I.A.; Gilad, D.; Herrmann, S.; Sekler, I.; Aizenman, E.; Hershfinkel, M. Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. J. Neurosci. 2011, 31, 12916–12926. [Google Scholar] [CrossRef] [Green Version]
  165. Kovacs, Z.; Schacht, T.; Herrmann, A.-K.; Albrecht, P.; Lefkimmiatis, K.; Methner, A. Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39. Biochem. J. 2014, 462, 125–132. [Google Scholar] [CrossRef] [PubMed]
  166. Jackson, V.R.; Nothacker, H.-P.; Civelli, O.O. GPR39 receptor expression in the mouse brain. Neuro Rep. 2006, 17, 813–816. [Google Scholar] [CrossRef]
  167. Hershfinkel, M. The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. Int. J. Mol. Sci. 2018, 19, 439. [Google Scholar] [CrossRef] [Green Version]
  168. Peixoto-Santos, J.E.; Galvis-Alonso, O.Y.; Velasco, T.R.; Kandratavicius, L.; Assirati, J.A.; Carlotti, C.G.; Scandiuzzi, R.C.; Neder Serafini, L.; Leite, J. Increased Metallothionein I/II Expression in Patients with Temporal Lobe Epilepsy. PLoS ONE 2012, 7, e44709. [Google Scholar] [CrossRef]
  169. Mollah, M.A.H.; Rakshit, S.C.; Anwar, K.S.; Arslan, M.I.; Saha, N.; Ahmed, S.; Azad, K.; Hassan, T. Zinc concentration in serum and cerebrospinal fluid simultaneously decrease in children with febrile seizure: Findings from a prospective study in Bangladesh. Acta Paediatr. 2008, 97, 1707–1711. [Google Scholar] [CrossRef]
  170. Farahani, H.N.; Ashthiani, A.R.; Masihi, M.S. Study on serum zinc and selenium levels in epileptic patients. Neuroscience 2013, 18, 138–142. [Google Scholar]
  171. Seven, M.; Basaran, S.Y.; Cengiz, M.; Unal, S.; Yuksel, A. Deficiency of selenium and zinc as a causative factor for idiopathic intractable epilepsy. Epilepsy Res. 2013, 104, 35–39. [Google Scholar] [CrossRef]
  172. Ni, H.; Jiang, Y.; Xiao, Z.-J.; Tao, L.-Y.; Jin, M.-F.; Wu, X.-R. Dynamic pattern of gene expression of ZnT-1, ZnT-3 and PRG-1 in rat brain following flurothyl-induced recurrent neonatal seizures. Toxicol. Lett. 2010, 194, 86–93. [Google Scholar] [CrossRef] [PubMed]
  173. Ni, H.; Feng, X.; Xiao, Z.-J.; Tao, L.-Y.; Jin, M.-F. Dynamic Pattern of Gene Expression of ZnT-4, Caspase-3, LC3, and PRG-3 in Rat Cerebral Cortex Following Flurothyl-Induced Recurrent Neonatal Seizures. Biol. Trace Element Res. 2011, 143, 1607–1615. [Google Scholar] [CrossRef] [PubMed]
  174. Ni, H.; Feng, X.; Gong, Y.; Tao, L.-Y.; Wu, X.-R. Acute Phase Expression Pattern of ZnTs, LC3, and Beclin-1 in Rat Hippocampus and Its Regulation by 3-Methyladenine Following Recurrent Neonatal Seizures. Biol. Trace Element Res. 2010, 143, 320–331. [Google Scholar] [CrossRef] [PubMed]
  175. Tian, T.; Ni, H.; Sun, B.-L. Neurobehavioral Deficits in a Rat Model of Recurrent Neonatal Seizures Are Prevented by a Ketogenic Diet and Correlate with Hippocampal Zinc/Lipid Transporter Signals. Biol. Trace Element Res. 2015, 167, 251–258. [Google Scholar] [CrossRef] [PubMed]
  176. Cole, T.B.; A Robbins, C.; Wenzel, H.; Schwartzkroin, P.; Palmiter, R.D. Seizures and neuronal damage in mice lacking vesicular zinc. Epilepsy Res. 2000, 39, 153–169. [Google Scholar] [CrossRef]
  177. McAllister, B.B.; Dyck, R.H. Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function. Neurosci. Biobehav. Rev. 2017, 80, 329–350. [Google Scholar] [CrossRef] [PubMed]
  178. Gilad, D.; Shorer, S.; Ketzef, M.; Friedman, A.; Sekler, I.; Aizenman, E.; Hershfinkel, M. Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures. Neurobiol. Dis. 2015, 81, 4–13. [Google Scholar] [CrossRef] [Green Version]
  179. Rivera, C.; Voipio, J.; Payne, J.A.; Ruusuvuori, E.; Lahtinen, H.; Lamsa, K.P.; Pirvola, U.; Saarma, M.; Kaila, K. The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nat. Cell Biol. 1999, 397, 251–255. [Google Scholar] [CrossRef]
  180. Zhu, L.; Lovinger, D.; Delpire, E. Cortical Neurons Lacking KCC2 Expression Show Impaired Regulation of Intracellular Chloride. J. Neurophysiol. 2005, 93, 1557–1568. [Google Scholar] [CrossRef] [Green Version]
  181. Woo, N.-S.; Lu, J.; England, R.; McClellan, R.; Dufour, S.; Mount, D.B.; Deutch, A.Y.; Lovinger, D.M.; Delpire, E. Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 2002, 12, 258–268. [Google Scholar] [CrossRef]
  182. Zhu, L.; Polley, N.; Mathews, G.C.; Delpire, E. NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy Res. 2008, 79, 201–212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Velíšková, J.; Claudio, O.I.; Galanopoulou, A.S.; Lado, F.A.; Ravizza, T.; Velíšek, L.; Moshé, S.L. Seizures in the Developing Brain. Epilepsia 2004, 45, 6–12. [Google Scholar] [CrossRef] [PubMed]
  184. Huberfeld, G.; Wittner, L.; Clemenceau, S.; Baulac, M.; Kaila, K.; Miles, R.; Rivera, C. Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy. J. Neurosci. 2007, 27, 9866–9873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Puskarjov, M.; Seja, P.; E Heron, S.; Williams, T.C.; Ahmad, F.; Iona, X.; Oliver, K.L.; Grinton, B.E.; Vutskits, L.; Scheffer, I.E.; et al. A variant of KCC 2 from patients with febrile seizures impairs neuronal Cl−extrusion and dendritic spine formation. EMBO Rep. 2014, 15, 723–729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Puskarjov, M.; Kahle, K.T.; Ruusuvuori, E.; Kaila, K. Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures. Epilepsia 2014, 55, 806–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Di Cristo, G.; Awad, P.N.; Hamidi, S.; Avoli, M. KCC2, epileptiform synchronization, and epileptic disorders. Prog. Neurobiol. 2018, 162, 1–16. [Google Scholar] [CrossRef]
  188. Kelley, M.R.; Cardarelli, R.A.; Smalley, J.L.; Ollerhead, T.A.; Andrew, P.M.; Brandon, N.J.; Deeb, T.Z.; Moss, S.J. Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy. EBioMedicine 2018, 32, 62–71. [Google Scholar] [CrossRef]
  189. Saadi, R.A.; He, K.; Hartnett, K.A.; Kandler, K.; Hershfinkel, M.; Aizenman, E. SNARE-dependent upregulation of potassium chloride co-transporter 2 activity after metabotropic zinc receptor activation in rat cortical neurons in vitro. Neuroscience 2012, 210, 38–46. [Google Scholar] [CrossRef] [Green Version]
  190. Khan, M.Z. A possible significant role of zinc and GPR39 zinc sensing receptor in Alzheimer disease and epilepsy. Biomed. Pharmacother. 2016, 79, 263–272. [Google Scholar] [CrossRef]
  191. Kasarskis, E.J.; Forrester, T.M.; Slevin, J.T. Amygdalar kindling is associated with elevated zinc concentration in the cortex and hippocampus of rats. Epilepsy Res. 1987, 1, 227–233. [Google Scholar] [CrossRef]
  192. Foresti, M.L.; Arisi, G.M.; Fernandes, A.; Tilelli, C.Q.; Garcia-Cairasco, N. Chelatable zinc modulates excitability and seizure duration in the amygdala rapid kindling model. Epilepsy Res. 2008, 79, 166–172. [Google Scholar] [CrossRef] [PubMed]
  193. Elsas, S.-M.; Hazany, S.; Gregory, W.L.; Mody, I. Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy. Epilepsia 2009, 50, 870–879. [Google Scholar] [CrossRef] [Green Version]
  194. Sterman, M.B.; Shouse, M.N.; Fairchild, M.; Belsito, O. Kindled seizure induction alters and is altered by zinc absorption. Brain Res. 1986, 383, 382–386. [Google Scholar] [CrossRef]
  195. Fukahori, M.; Itoh, M. Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in theEl (epilepsy) mouse. Brain Res. 1990, 529, 16–22. [Google Scholar] [CrossRef]
  196. Takeda, A.; Hirate, M.; Tamano, H.; Nisibaba, D.; Oku, N. Susceptibility to kainate-induced seizures under dietary zinc deficiency. J. Neurochem. 2003, 85, 1575–1580. [Google Scholar] [CrossRef]
  197. Takeda, A.; Tamano, H.; Oku, N. Involvement of unusual glutamate release in kainate-induced seizures in zinc-deficient adult rats. Epilepsy Res. 2005, 66, 137–143. [Google Scholar] [CrossRef]
  198. Takeda, A.; Itoh, H.; Hirate, M.; Oku, N. Region-specific loss of zinc in the brain in pentylentetrazole-induced seizures and seizure susceptibility in zinc deficiency. Epilepsy Res. 2006, 70, 41–48. [Google Scholar] [CrossRef]
  199. Takeda, A.; Iida, M.; Ando, M.; Nakamura, M.; Tamano, H.; Oku, N. Enhanced Susceptibility to Spontaneous Seizures of Noda Epileptic Rats by Loss of Synaptic Zn2+. PLoS ONE 2013, 8, e71372. [Google Scholar] [CrossRef]
  200. Kumar, H.; Katyal, J.; Gupta, Y.K. Low Dose Zinc Supplementation Beneficially Affects Seizure Development in Experimental Seizure Models in Rats. Biol. Trace Element Res. 2014, 163, 208–216. [Google Scholar] [CrossRef]
  201. Khanna, N.; Garg, A.; Sharma, K.K.; Khosla, R. Modulation of convulsive threshold of pentylene tetrazole by zinc. Indian J. Clin. Biochem. 1997, 12, 86–90. [Google Scholar] [CrossRef] [Green Version]
  202. Zhu, L.; Ji, X.-J.; Wang, H.-D.; Pan, H.; Chen, M.; Lu, T.-J. Zinc neurotoxicity to hippocampal neurons in vitro induces ubiquitin conjugation that requires p38 activation. Brain Res. 2012, 1438, 1–7. [Google Scholar] [CrossRef] [PubMed]
  203. Baraka, A.M.; El Nabi, W.H.; El Ghotni, S. Investigating the Role of Zinc in a Rat Model of Epilepsy. CNS Neurosci. Ther. 2011, 18, 327–333. [Google Scholar] [CrossRef] [PubMed]
  204. Gao, H.; Boillat, A.; Huang, D.; Liang, C.; Peers, C.; Gamper, N. Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate. Proc. Natl. Acad. Sci. USA 2017, 114, E6410–E6419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Alterio, V.; Pan, P.; Parkkila, S.; Buonanno, M.; Supuran, C.T.; Monti, S.M.; De Simone, G. The structural comparison between membrane-associated human carbonic anhydrases provides insights into drug design of selective inhibitors. Biopolymers 2014, 101, 769–778. [Google Scholar] [CrossRef]
  206. Boone, C.D.; Pinard, M.; McKenna, R.; Silverman, D. Catalytic Mechanism of α-Class Carbonic Anhydrases: CO2 Hydration and Proton Transfer. Subcell. Biochem. 2013, 75, 31–52. [Google Scholar] [CrossRef]
  207. Bruno, E.; Buemi, M.R.; De Luca, L.; Ferro, S.; Monforte, A.-M.; Supuran, C.T.; Vullo, D.; De Sarro, G.; Russo, E.; Gitto, R. In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents. ChemMedChem 2016, 11, 1812–1818. [Google Scholar] [CrossRef]
  208. Lomelino, C.L.; Supuran, C.T.; McKenna, R. Non-Classical Inhibition of Carbonic Anhydrase. Int. J. Mol. Sci. 2016, 17, 1150. [Google Scholar] [CrossRef] [Green Version]
  209. Ghandour, M.S.; Parkkila, A.-K.; Parkkila, S.; Waheed, A.; Sly, W.S. Mitochondrial Carbonic Anhydrase in the Nervous System. J. Neurochem. 2002, 75, 2212–2220. [Google Scholar] [CrossRef]
  210. Tong, C.-K.; Brion, L.P.; Suárez, C.; Chesler, M. Interstitial Carbonic Anhydrase (CA) Activity in Brain Is Attributable to Membrane-Bound CA Type IV. J. Neurosci. 2000, 20, 8247–8253. [Google Scholar] [CrossRef] [Green Version]
  211. Ruusuvuori, E.; Li, H.; Huttu, K.; Palva, S.; Smirnov, S.Y.; Rivera, C.; Kaila, K.; Voipio, J. Carbonic Anhydrase Isoform VII Acts as a Molecular Switch in the Development of Synchronous Gamma-Frequency Firing of Hippocampal CA1 Pyramidal Cells. J. Neurosci. 2004, 24, 2699–2707. [Google Scholar] [CrossRef]
  212. Ruusuvuori, E.; Kaila, K. Carbonic Anhydrases and Brain pH in the Control of Neuronal Excitability. Subcell. Biochem. 2014, 75, 271–290. [Google Scholar] [CrossRef] [PubMed]
  213. Kaila, K.; Ruusuvuori, E.; Seja, P.; Voipio, J.; Puskarjov, M. GABA actions and ionic plasticity in epilepsy. Curr. Opin. Neurobiol. 2014, 26, 34–41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  214. Phillips, I.; Martin, K.F.; Thompson, K.S.; Heal, D.J. GABA-evoked depolarisations in the rat cortical wedge: Involvement of GABAA receptors and HCO3− ions. Brain Res. 1998, 798, 330–332. [Google Scholar] [CrossRef]
  215. Datta, R.; Waheed, A.; Bonapace, G.; Shah, G.N.; Sly, W.S. Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV. Proc. Natl. Acad. Sci. USA 2009, 106, 3437–3442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Battke, C.; Kremmer, E.; Mysliwietz, J.; Gondi, G.; Dumitru, C.; Brandau, S.; Lang, S.; Vullo, D.; Supuran, C.; Zeidler, R. Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol. Immunother. 2011, 60, 649–658. [Google Scholar] [CrossRef]
  217. Hen, N.; Bialer, M.; Yagen, B.; Maresca, A.; Aggarwal, M.; Robbins, A.H.; McKenna, R.; Scozzafava, A.; Supuran, C.T. Anticonvulsant 4-Aminobenzenesulfonamide Derivatives with Branched-Alkylamide Moieties: X-ray Crystallography and Inhibition Studies of Human Carbonic Anhydrase Isoforms I, II, VII, and XIV. J. Med. Chem. 2011, 54, 3977–3981. [Google Scholar] [CrossRef] [PubMed]
  218. Supuran, C.T. Carbonic anhydrase inhibitors as emerging drugs for the treatment of obesity. Expert Opin. Emerg. Drugs 2012, 17, 11–15. [Google Scholar] [CrossRef]
  219. Scozzafava, A.; Supuran, C.T. Glaucoma and the Applications of Carbonic Anhydrase Inhibitors. Subcell. Biochem. 2013, 75, 349–359. [Google Scholar] [CrossRef]
  220. Çavuş, I.; Romanyshyn, J.C.; Kennard, J.T.; Farooque, P.; Williamson, A.; Eid, T.; Spencer, S.S.; Duckrow, R.; Dziura, J.; Spencer, D.D. Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program. Ann. Neurol. 2016, 80, 35–45. [Google Scholar] [CrossRef]
  221. Luna-Munguia, H.; Zestos, A.G.; Gliske, S.V.; Kennedy, R.T.; Stacey, W. Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy. Neurobiol. Dis. 2019, 121, 177–186. [Google Scholar] [CrossRef]
  222. Xiong, Z.-Q.; Stringer, J.L. Regulation of extracellular pH in the developing hippocampus. Dev. Brain Res. 2000, 122, 113–117. [Google Scholar] [CrossRef]
  223. Koch, A.; Woodbury, D.M. Effects of carbonic anhydrase inhibition of brain excitability. J. Pharmacol. Exp. Ther 1958, 122, 335–342. [Google Scholar] [PubMed]
  224. Szaflarski, J. University of Alabama at Birmingham and the UAB Epilepsy Center th Avenue South CIRC Birmingham AL USA Cannabis For The Treatment Of Epilepsy. Planta Medica 2016, 82, 1284–1289. [Google Scholar] [CrossRef]
  225. Rauh, C.E.; Gray, W.D. The anticonvulsant potency of inhibitors of carbonic anhydrase in young and adult rats and mice. J. Pharmacol. Exp. Ther. 1968, 161, 329–334. [Google Scholar]
  226. Shank, R.P.; Gardocki, J.F.; Vaught, J.L.; Davis, C.B.; Schupsky, J.J.; Raffa, R.B.; Dodgson, S.J.; Nortey, S.O.; Maryanoff, B.E. Topiramate: Preclinical Evaluation of a Structurally Novel Anticonvulsant. Epilepsia 1994, 35, 450–460. [Google Scholar] [CrossRef]
  227. Ben-Menachem, E.; Henriksen, O.; Dam, M.; Mikkelsen, M.; Schmidt, D.; Reid, S.; Reife, R.; Kramer, L.; Pledger, G.; Karim, R. Double-Blind, Placebo-Controlled Trial of Topiramate as Add-on Therapy in Patients with Refractory Partial Seizures. Epilepsia 1996, 37, 539–543. [Google Scholar] [CrossRef]
  228. Wilensky, A.J.; Friel, P.N.; Ojemann, L.M.; Dodrill, C.B.; McCormick, K.B.; Levy, R.H. Zonisamide in Epilepsy: A Pilot Study. Epilepsia 1985, 26, 212–220. [Google Scholar] [CrossRef]
  229. Nakamura, J.; Tamura, S.; Kanda, T.; Ishii, A.; Ishihara, K.; Serikawa, T.; Yamada, J.; Sasa, M. Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice. Eur. J. Pharmacol. 1994, 254, 83–89. [Google Scholar] [CrossRef]
  230. Masereel, B.; Rolin, S.; Abbate, F.; Scozzafava, A.; Supuran, C.T. Carbonic Anhydrase Inhibitors: Anticonvulsant Sulfonamides Incorporating Valproyl and Other Lipophilic Moieties. J. Med. Chem. 2002, 45, 312–320. [Google Scholar] [CrossRef]
  231. Supuran, C.T.; Scozzafava, A.; Casini, A. Carbonic anhydrase inhibitors. Med. Res. Rev. 2003, 23, 146–189. [Google Scholar] [CrossRef]
  232. Aggarwal, M.; Kondeti, B.; McKenna, R. Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: A patent review. Expert Opin. Ther. Pat. 2013, 23, 717–724. [Google Scholar] [CrossRef] [PubMed]
  233. Halmi, P.; Parkkila, S.; Honkaniemi, J. Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. Neurochem. Int. 2006, 48, 24–30. [Google Scholar] [CrossRef] [PubMed]
  234. Bootorabi, F.; Jänis, J.; Smith, E.; Waheed, A.; Kukkurainen, S.; Hytönen, V.P.; Valjakka, J.; Supuran, C.T.; Vullo, D.; Sly, W.S.; et al. Analysis of a shortened form of human carbonic anhydrase VII expressed in vitro compared to the full-length enzyme. Biochimie 2010, 92, 1072–1080. [Google Scholar] [CrossRef] [PubMed]
  235. Ruusuvuori, E.; Huebner, A.K.; Kirilkin, I.; Yukin, A.Y.; Blaesse, P.; Helmy, M.; Kang, H.J.; El Muayed, M.; Hennings, J.C.; Voipio, J.; et al. Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures. EMBO J. 2013, 32, 2275–2286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Gavernet, L.; Funes, J.L.G.; Palestro, P.H.; Blanch, L.E.B.; Estiu, G.L.; Maresca, A.; Barrios, I.; Supuran, C.T. Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV. Bioorganic Med. Chem. 2013, 21, 1410–1418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  237. Villalba, M.L.; Palestro, P.; Ceruso, M.; Funes, J.L.G.; Talevi, A.; Blanch, L.B.; Supuran, C.T.; Gavernet, L. Sulfamide derivatives with selective carbonic anhydrase VII inhibitory action. Bioorganic Med. Chem. 2016, 24, 894–901. [Google Scholar] [CrossRef]
  238. De Luca, L.; Ferro, S.; Damiano, F.M.; Supuran, C.T.; Vullo, D.; Chimirri, A.; Gitto, R. Structure-based screening for the discovery of new carbonic anhydrase VII inhibitors. Eur. J. Med. Chem. 2014, 71, 105–111. [Google Scholar] [CrossRef]
  239. Jelkmann, W. Molecular Biology of Erythropoietin. Intern. Med. 2004, 43, 649–659. [Google Scholar] [CrossRef] [Green Version]
  240. Sinclair, A.M. Erythropoiesis stimulating agents: Approaches to modulate activity. Biol. Targets Ther. 2013, 7, 161–174. [Google Scholar] [CrossRef] [Green Version]
  241. Chikuma, M.; Masuda, S.; Kobayashi, T.; Nagao, M.; Sasaki, R. Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am. J. Physiol. Metab. 2000, 279, E1242–E1248. [Google Scholar] [CrossRef]
  242. Bunn, H.F. Erythropoietin. Cold Spring Harb. Perspect. Med. 2013, 3, a011619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  243. Depping, R.; Kawakami, K.; Ocker, H.; Wagner, J.M.; Heringlake, M.; Noetzold, A.; Sievers, H.-H.; Wagner, K.F. Expression of the erythropoietin receptor in human heart. J. Thorac. Cardiovasc. Surg. 2005, 130, 877–878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  244. Yasuda, Y.; Masuda, S.; Chikuma, M.; Inoue, K.; Nagao, M.; Sasaki, R. Estrogen-dependent Production of Erythropoietin in Uterus and Its Implication in Uterine Angiogenesis. J. Biol. Chem. 1998, 273, 25381–25387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  245. Juul, S.E.; Yachnis, A.T.; Rojiani, A.M.; Christensen, R.D. Immunohistochemical Localization of Erythropoietin and Its Receptor in the Developing Human Brain. Pediatr. Dev. Pathol. 1999, 2, 148–158. [Google Scholar] [CrossRef]
  246. Lappin, T.R. The Cellular Biology of Erythropoietin Receptors. Oncologist 2003, 8, 15–18. [Google Scholar] [CrossRef]
  247. Morishita, E.; Masuda, S.; Nagao, M.; Yasuda, Y.; Sasaki, R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 1996, 76, 105–116. [Google Scholar] [CrossRef]
  248. Bernaudin, M.; Marti, H.H.; Roussel, S.; Divoux, D.; Nouvelot, A.; MacKenzie, E.T.; Petit, E. A Potential Role for Erythropoietin in Focal Permanent Cerebral Ischemia in Mice. Br. J. Pharmacol. 1999, 19, 643–651. [Google Scholar] [CrossRef] [Green Version]
  249. Chin, K.; Yu, X.; Beleslin-Cokic, B.; Liu, C.; Shen, K.; Mohrenweiser, H.W.; Noguchi, C.T. Production and processing of erythropoietin receptor transcripts in brain. Mol. Brain Res. 2000, 81, 29–42. [Google Scholar] [CrossRef]
  250. Noguchi, C.T.; Asavaritikrai, P.; Teng, R.; Jia, Y. Role of erythropoietin in the brain. Crit. Rev. Oncol. 2007, 64, 159–171. [Google Scholar] [CrossRef] [Green Version]
  251. Rabie, T.; Marti, H.H. Brain Protection by Erythropoietin: A Manifold Task. Physiology 2008, 23, 263–274. [Google Scholar] [CrossRef] [Green Version]
  252. Sanchez, P.E.; Fares, R.P.; Risso, J.-J.; Bonnet, C.; Bouvard, S.; Le-Cavorsin, M.; Georges, B.; Moulin, C.; Belmeguenai, A.; Bodennec, J.; et al. Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons. Proc. Natl. Acad. Sci. USA 2009, 106, 9848–9853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  253. Konishi, Y.; Chui, D.-H.; Hirose, H.; Kunishita, T.; Tabira, T. Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res. 1993, 609, 29–35. [Google Scholar] [CrossRef]
  254. Sakanaka, M.; Wen, T.-C.; Matsuda, S.; Morishita, E.; Nagao, M.; Sasaki, R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. USA 1998, 95, 4635–4640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  255. Brines, M.; Ghezzi, P.; Keenan, S.; Agnello, D.; De Lanerolle, N.C.; Cerami, C.; Itri, L.M.; Cerami, A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. USA 2000, 97, 10526–10531. [Google Scholar] [CrossRef] [Green Version]
  256. Sirén, A.-L.; Fratelli, M.; Brines, M.; Goemans, C.; Casagrande, S.; Lewczuk, P.; Keenan, S.; Gleiter, C.; Pasquali, C.; Capobianco, A.; et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. USA 2001, 98, 4044–4049. [Google Scholar] [CrossRef] [Green Version]
  257. Wen, T.-C.; Sadamoto, Y.; Tanaka, J.; Zhu, P.-X.; Nakata, K.; Ma, Y.-J.; Hata, R.; Sakanaka, M. Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J. Neurosci. Res. 2002, 67, 795–803. [Google Scholar] [CrossRef]
  258. Chong, Z.Z.; Kang, J.-Q.; Maiese, K. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br. J. Pharmacol. 2003, 138, 1107–1118. [Google Scholar] [CrossRef] [Green Version]
  259. Mikati, M.A.; El Hokayem, J.A.; El Sabban, M.E. Effects of a Single Dose of Erythropoietin on Subsequent Seizure Susceptibility in Rats Exposed to Acute Hypoxia at P10. Epilepsia 2007, 48, 175–181. [Google Scholar] [CrossRef]
  260. Chu, K.; Jung, K.-H.; Lee, S.-T.; Kim, J.; Kang, K.-M.; Kim, H.-K.; Park, Y.H.; Park, H.-K.; Kim, M.; Lee, S.K.; et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008, 49, 1723–1732. [Google Scholar] [CrossRef]
  261. Carelli, S.; Giallongo, T.; Viaggi, C.; Latorre, E.; Gombalova, Z.; Raspa, A.; Mazza, M.; Vaglini, F.; Di Giulio, A.M.; Gorio, A. Recovery from experimental parkinsonism by intrastriatal application of erythropoietin or EPO-releasing neural precursors. Neuropharmacol. 2017, 119, 76–90. [Google Scholar] [CrossRef]
  262. Tamura, T.; Aoyama, M.; Ukai, S.; Kakita, H.; Sobue, K.; Asai, K. Neuroprotective erythropoietin attenuates microglial activation, including morphological changes, phagocytosis, and cytokine production. Brain Res. 2017, 1662, 65–74. [Google Scholar] [CrossRef] [PubMed]
  263. Yip, H.-K.; Tsai, T.-H.; Lin, H.-S.; Cheng-Hsien, L.; Sun, C.-K.; Leu, S.; Yuen, C.-M.; Tan, T.-Y.; Lan, M.-Y.; Liou, C.-W.; et al. Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit. Care 2011, 15, R40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  264. Wustenberg, T.; Begemann, M.; Bartels, C.; Gefeller, O.; Stawicki, S.; Hinze-Selch, D.; Mohr, A.; Falkai, P.; Aldenhoff, J.B.; Knauth, M.; et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol. Psychiatry 2010, 16, 26–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  265. Jang, W.; Park, J.; Shin, K.J.; Kim, J.-S.; Kim, J.S.; Youn, J.; Cho, J.W.; Oh, E.; Ahn, J.Y.; Oh, K.-W.; et al. Safety and efficacy of recombinant human erythropoietin treatment of non-motor symptoms in Parkinson’s disease. J. Neurol. Sci. 2014, 337, 47–54. [Google Scholar] [CrossRef] [PubMed]
  266. Kadota, T.; Shingo, T.; Yasuhara, T.; Tajiri, N.; Kondo, A.; Morimoto, T.; Yuan, W.J.; Wang, F.; Baba, T.; Tokunaga, K.; et al. Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson’s disease model of rats with enhanced neurogenesis. Brain Res. 2009, 1254, 120–127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  267. Garzón, F.; Coimbra, D.; Parcerisas, A.; Rodriguez, Y.; García, J.C.; Soriano, E.; Rama, R. NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. J. Alzheimer’s Dis. 2018, 65, 1469–1483. [Google Scholar] [CrossRef]
  268. Im, J.H.; Yeo, I.J.; Hwang, C.J.; Lee, K.S.; Hong, J.T. PEGylated Erythropoietin Protects against Brain Injury in the MCAO-Induced Stroke Model by Blocking NF-κB Activation. Biomol. Ther. 2020, 28, 152–162. [Google Scholar] [CrossRef]
  269. Renzi, M.J.; Farrell, F.X.; Bittner, A.; Galindo, J.E.; Morton, M.; Trinh, H.; Jolliffe, L.K. Erythropoietin induces changes in gene expression in PC-12 cells. Mol. Brain Res. 2002, 104, 86–95. [Google Scholar] [CrossRef]
  270. Chu, H.; Ding, H.; Tang, Y.; Dong, Q. Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4. Lab. Investig. 2014, 94, 1042–1053. [Google Scholar] [CrossRef] [Green Version]
  271. Wei, S.; Luo, C.; Yu, S.P.; Gao, J.; Liu, C.; Wei, Z.Z.; Zhang, Z.; Wei, L.; Yi, B. Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway. Exp. Cell Res. 2017, 361, 342–352. [Google Scholar] [CrossRef]
  272. Koshimura, K.; Murakami, Y.; Sohmiya, M.; Tanaka, J.; Kato, Y. Effects of erythropoietin on neuronal activity. J. Neurochem. 1999, 72, 2565–2572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  273. Masuda, S.; Nagao, M.; Takahata, K.; Konishi, Y.; Gallyas, F.; Tabira, T.; Sasaki, R. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J. Biol. Chem. 1993, 268, 11208–11216. [Google Scholar] [PubMed]
  274. Kondo, A.; Shingo, T.; Yasuhara, T.; Kuramoto, S.; Kameda, M.; Kikuchi, Y.; Matsui, T.; Miyoshi, Y.; Agari, T.; Borlongan, C.V.; et al. Erythropoietin exerts anti-epileptic effects with the suppression of aberrant new cell formation in the dentate gyrus and upregulation of neuropeptide Y in seizure model of rats. Brain Res. 2009, 1296, 127–136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  275. Üzüm, G.; Diler, A.S.; Bahçekapılı, N.; Ziylan, Y.Z. Erythropoietin prevents the increase in blood–brain barrier permeability during pentylentetrazol induced seizures. Life Sci. 2006, 78, 2571–2576. [Google Scholar] [CrossRef]
  276. Bahçekapılı, N.; Akgun-Dar, K.; Albeniz, I.; Kapucu, A.; Kandil, A.; Yağız, O.; Üzüm, G.; Bahcekapili, N.; Kandil, A.; Yagiz, O. Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole-induced generalized seizures. Int. J. Neurosci. 2014, 124, 762–770. [Google Scholar] [CrossRef]
  277. Nadam, J.; Navarro, F.; Sánchez, P.; Moulin, C.; Georges, B.; Laglaine, A.; Pequignot, J.-M.; Morales, A.; Ryvlin, P.; Bezin, L. Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol. Dis. 2007, 25, 412–426. [Google Scholar] [CrossRef] [Green Version]
  278. Sözmen, Ş.Ç.; Kurul, S.H.; Yiş, U.; Tuğyan, K.; Baykara, B.; Yılmaz, O. Neuroprotective effects of recombinant human erythropoietin in the developing brain of rat after lithium-pilocarpine induced status epilepticus. Brain Dev. 2012, 34, 189–195. [Google Scholar] [CrossRef]
  279. Seeger, N.; Zellinger, C.; Rode, A.; Roloff, F.; Bicker, G.; Russmann, V.; Fischborn, S.; Wendt, H.; Potschka, H. The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model. Epilepsia 2011, 52, 2333–2343. [Google Scholar] [CrossRef]
  280. Zellinger, C.; Seeger, N.; Hadamitzky, M.; Fischborn, S.; Russmann, V.; Wendt, H.; Pankratova, S.; Bock, E.; Berezin, V.; Potschka, H. Impact of the erythropoietin-derived peptide mimetic Epotris on the histopathological consequences of status epilepticus. Epilepsy Res. 2011, 96, 241–249. [Google Scholar] [CrossRef]
  281. Ott, C.; Martens, H.; Hassouna, I.; Oliveira, B.; Erck, C.; Zafeiriou, M.-P.; Peteri, U.-K.; Hesse, D.; Gerhart, S.; Altas, B.; et al. Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury. Mol. Med. 2015, 21, 803–815. [Google Scholar] [CrossRef]
  282. Yang, J.; Huang, Y.; Yu, X.; Sun, H.; Li, Y.; Deng, Y. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol. Exp. 2007, 67, 141–148. [Google Scholar]
  283. Kilic, E.; Kilic, Ü.; Soliz, J.; Bassetti, C.L.; Gassmann, M.; Hermann, D.M. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. FASEB J. 2005, 19, 2026–2028. [Google Scholar] [CrossRef] [PubMed]
  284. Du, Y.-Z.; Gu, X.-H.; Cheng, S.-F.; Li, L.; Liu, H.; Hu, L.-P.; Gao, F. The oncogenetic role of stanniocalcin 1 in lung adenocarcinoma: A promising serum candidate biomarker for tracking lung adenocarcinoma progression. Tumor Biol. 2015, 37, 5633–5644. [Google Scholar] [CrossRef] [PubMed]
  285. Meldrum, B.S. Prolonged Epileptic Seizures in Primates. Arch. Neurol. 1973, 28, 10–17. [Google Scholar] [CrossRef] [PubMed]
  286. Moseley, B.D.; Nickels, K.; Britton, J.; Wirrell, E. How common is ictal hypoxemia and bradycardia in children with partial complex and generalized convulsive seizures? Epilepsia 2010, 51, 1219–1224. [Google Scholar] [CrossRef]
  287. Luna-Munguia, H.; Orozco-Suã¡rez, S.; Rocha, L. Effects of high frequency electrical stimulation and R-verapamil on seizure susceptibility and glutamate and GABA release in a model of phenytoin-resistant seizures. Neuropharmacology 2011, 61, 807–814. [Google Scholar] [CrossRef]
  288. Socodato, R.; Portugal, C.C.; Rodrigues, A.; Henriques, J.; Rodrigues, C.; Figueira, C.; Relvas, J.B. Redox tuning of Ca 2+ signaling in microglia drives glutamate release during hypoxia. Free. Radic. Biol. Med. 2018, 118, 137–149. [Google Scholar] [CrossRef]
  289. Erecińska, M.; Silver, I.A. Tissue oxygen tension and brain sensitivity to hypoxia. Respir. Physiol. 2001, 128, 263–276. [Google Scholar] [CrossRef]
  290. Gorter, J.A.; Pereira, P.M.G.; Van Vliet, E.A.; Aronica, E.; Da Silva, F.H.L.; Lucassen, P.J. Neuronal Cell Death in a Rat Model for Mesial Temporal Lobe Epilepsy Is Induced by the Initial Status Epilepticus and Not by Later Repeated Spontaneous Seizures. Epilepsia 2003, 44, 647–658. [Google Scholar] [CrossRef] [Green Version]
  291. Weir, E.K.; Olschewski, A. Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia. Cardiovasc. Res. 2006, 71, 630–641. [Google Scholar] [CrossRef] [Green Version]
  292. Auzmendi, J.; Akyuz, E.; Lazarowski, A. The role of P-glycoprotein (P-gp) and inwardly rectifying potassium (Kir) channels in sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2019, 106590. [Google Scholar] [CrossRef]
  293. Callaghan, R.; Crowley, E.; Biochem, M.; Potter, S.; Kerr, I.D. P-glycoprotein: So Many Ways to Turn It On. J. Clin. Pharmacol. 2008, 48, 365–378. [Google Scholar] [CrossRef] [PubMed]
  294. Avemary, J.; Salvamoser, J.D.; Peraud, A.; Rémi, J.; Noachtar, S.; Fricker, G.; Potschka, H. Dynamic Regulation of P-glycoprotein in Human Brain Capillaries. Mol. Pharm. 2013, 10, 3333–3341. [Google Scholar] [CrossRef] [PubMed]
  295. Mattson, M.P. Free Radicals, Calcium., and The Synaptic Plasticity-Cell Death Continuum: Emerging Roles of The Transcription Factor Nfκb. Int. Rev. Neurobiol. 1998, 42, 103–168. [Google Scholar] [CrossRef]
  296. Auzmendi, J.; Orozco-Suã¡rez, S.; Bañuelos-Cabrera, I.; González-Trujano, M.E.; González, E.C.; Rocha, L.; Lazarowski, A. P-Glycoprotein Contributes to Cell Membrane Depolarization of Hippocampus and Neocortex in a Model of Repetitive Seizures Induced by Pentylenetetrazole in Rats. Curr. Pharm. Des. 2013, 19, 6732–6738. [Google Scholar] [CrossRef]
  297. Marti, H.H. Erythropoietin and the hypoxic brain. J. Exp. Biol. 2004, 207, 3233–3242. [Google Scholar] [CrossRef] [Green Version]
  298. Nicoletti, J.; Shah, S.; McCloskey, D.P.; Goodman, J.; Elkady, A.; Atassi, H.; Hylton, D.; Rudge, J.; Scharfman, H.; Croll, S.D. Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience 2008, 151, 232–241. [Google Scholar] [CrossRef] [Green Version]
  299. Feast, A.; Martinian, L.; Liu, J.; Catarino, C.B.; Thom, M.; Sisodiya, S.M. Investigation of hypoxia-inducible factor-1α in hippocampal sclerosis: A postmortem study. Epilepsia 2012, 53, 1349–1359. [Google Scholar] [CrossRef]
  300. Haase, V.H. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013, 27, 41–53. [Google Scholar] [CrossRef]
  301. Merelli, A.; Czornyj, L.; Lazarowski, A. Erythropoietin: A Neuroprotective Agent in Cerebral Hypoxia, Neurodegeneration, and Epilepsy. Curr. Pharm. Des. 2013, 19, 6791–6801. [Google Scholar] [CrossRef]
  302. McPherson, R.J.; Juul, S.E. Recent trends in erythropoietin-mediated neuroprotection. Int. J. Dev. Neurosci. 2007, 26, 103–111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  303. Tomsig, J.L.; Creutz, C.E. Copines: A ubiquitous family of Ca 2+ -dependent phospholipid-binding proteins. Cell. Mol. Life Sci. 2002, 59, 1467–1477. [Google Scholar] [CrossRef] [PubMed]
  304. Nalefski, E.A.; Falke, J.J. The C2 domain calcium-binding motif: Structural and functional diversity. Protein Sci. 1996, 5, 2375–2390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  305. Creutz, C.E.; Tomsig, J.L.; Snyder, S.L.; Gautier, M.-C.; Skouri, F.; Beisson, J.; Cohen, J. The Copines, a Novel Class of C2 Domain-containing, Calciumdependent, Phospholipid-binding Proteins Conserved fromParameciumto Humans. J. Biol. Chem. 1998, 273, 1393–1402. [Google Scholar] [CrossRef] [Green Version]
  306. Tomsig, J.L. Identification of Targets for Calcium Signaling through the Copine Family of Proteins. Characterization of a coiled-coil copine-binding motif. J. Biol. Chem. 2003, 278, 10048–10054. [Google Scholar] [CrossRef] [Green Version]
  307. Nakayama, T.; Yaoi, T.; Yasui, M.; Kuwajima, G. N-copine: A novel two C2-domain-containing protein with neuronal activity-regulated expression. FEBS Lett. 1998, 428, 80–84. [Google Scholar] [CrossRef] [Green Version]
  308. Savino, M.; D’Apolito, M.; Centra, M.; Van Beerendonk, H.M.; Cleton-Jansen, A.-M.; Whitmore, S.A.; Crawford, J.; Callen, D.F.; Zelante, L.; Savoia, A. Characterization of Copine VII, a New Member of the Copine Family, and Its Exclusion as a Candidate in Sporadic Breast Cancers with Loss of Heterozygosity at 16q24.3. Genomics 1999, 61, 219–226. [Google Scholar] [CrossRef]
  309. Tomsig, J.L.; Creutz, C.E. Biochemical Characterization of Copine: A Ubiquitous Ca2+-Dependent, Phospholipid-Binding Protein. Biochemistry 2000, 39, 16163–16175. [Google Scholar] [CrossRef]
  310. Cowland, J.B.; Carter, D.; Bjerregaard, M.D.; Johnsen, A.H.; Borregaard, N.; Lollike, K. Tissue expression of copines and isolation of copines I and III from the cytosol of human neutrophils. J. Leukoc. Biol. 2003, 74, 379–388. [Google Scholar] [CrossRef]
  311. Maitra, R.; Grigoryev, D.; Bera, T.K.; Pastan, I.; Lee, B. Cloning, molecular characterization, and expression analysis of Copine 8. Biochem. Biophys. Res. Commun. 2003, 303, 842–847. [Google Scholar] [CrossRef] [Green Version]
  312. Perestenko, P.V.; Pooler, A.M.; Noorbakhshnia, M.; Gray, A.; Bauccio, C.; McIlhinney, R.A.J. Copines-1, -2, -3, -6 and -7 show different calcium-dependent intracellular membrane translocation and targeting. FEBS J. 2010, 277, 5174–5189. [Google Scholar] [CrossRef] [PubMed]
  313. Liu, S.; Tang, H.; Zhu, J.; Ding, H.; Zeng, Y.; Du, W.; Ding, Z.; Song, P.; Zhang, Y.; Liu, Z.; et al. High expression of Copine 1 promotes cell growth and metastasis in human lung adenocarcinoma. Int. J. Oncol. 2018, 53, 2369–2378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  314. Corbalan-Garcia, S.; Gomez-Fernández, J.C. Signaling through C2 domains: More than one lipid target. Biochim. Biophys. Acta 2014, 1838, 1536–1547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  315. Goel, M.; Li, T.; Badea, T.C. Differential expression and subcellular localization of Copines in mouse retina. J. Comp. Neurol. 2019, 527, 2245–2262. [Google Scholar] [CrossRef]
  316. Reinhard, J.R.; Kriz, A.; Galic, M.; Angliker, N.; Rajalu, M.; Vogt, K.E.; Rüegg, M.A. The calcium sensor Copine-6 regulates spine structural plasticity and learning and memory. Nat. Commun. 2016, 7, 11613. [Google Scholar] [CrossRef] [Green Version]
  317. Burk, K.; Ramachandran, B.; Ahmed, S.; Hurtado-Zavala, J.I.; Awasthi, A.; Benito, E.; Faram, R.; Ahmad, H.; Swaminathan, A.; McIlhinney, J.; et al. Regulation of Dendritic Spine Morphology in Hippocampal Neurons by Copine-6. Cereb. Cortex 2017, 28, 1087–1104. [Google Scholar] [CrossRef]
  318. Kaufmann, W.E. Dendritic Anomalies in Disorders Associated with Mental Retardation. Cereb. Cortex 2000, 10, 981–991. [Google Scholar] [CrossRef]
  319. Pfeiffer, B.E.; Huber, K.M. The State of Synapses in Fragile X Syndrome. Neuroscience 2009, 15, 549–567. [Google Scholar] [CrossRef]
  320. Nishiyama, J. Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders. Psychiatry Clin. Neurosci. 2019, 73, 541–550. [Google Scholar] [CrossRef]
  321. Selkoe, D.J. Alzheimer’s Disease Is a Synaptic Failure. Science 2002, 298, 789–791. [Google Scholar] [CrossRef] [Green Version]
  322. Wilke, S.A.; Raam, T.; Antonios, J.K.; Bushong, E.A.; Koo, E.H.; Ellisman, M.H.; Ghosh, A. Specific Disruption of Hippocampal Mossy Fiber Synapses in a Mouse Model of Familial Alzheimer’s Disease. PLoS ONE 2014, 9, e84349. [Google Scholar] [CrossRef]
  323. Calabresi, P.; Picconi, B.; Parnetti, L.; Di Filippo, M. A convergent model for cognitive dysfunctions in Parkinson’s disease: The critical dopamine–acetylcholine synaptic balance. Lancet Neurol. 2006, 5, 974–983. [Google Scholar] [CrossRef]
  324. Murphy, B.L.; Hofacer, R.D.; Faulkner, C.N.; Loepke, A.W.; Danzer, S.C. Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis. Epilepsia 2012, 53, 908–921. [Google Scholar] [CrossRef] [Green Version]
  325. Singh, S.P.; He, X.; McNamara, J.O.; Danzer, S.C. Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis. Hippocampus 2013, 23, 1309–1320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  326. Thomas, P.; Phillips, J.; Delanty, N.; O’Connor, W. Elevated extracellular levels of glutamate, aspartate and gamma-aminobutyric acid within the intraoperative, spontaneously epileptiform human hippocampus. Epilepsy Res. 2003, 54, 73–79. [Google Scholar] [CrossRef]
  327. Thomas, P.M.; Phillips, J.P.; O’Connor, W.T. Hippocampal microdialysis during spontaneous intraoperative epileptiform activity. Acta Neurochir. 2004, 146, 143–151. [Google Scholar] [CrossRef]
  328. Ben-Ari, Y. Cell death and synaptic reorganizations produced by seizures. Epilepsia 2001, 42, 5–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  329. Sutula, T.; Dudek, F.E. Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: An emergent property of a complex system. Prog. Brain Res. 2007, 163, 541–563. [Google Scholar] [CrossRef]
  330. Nakayama, T.; Yaoi, T.; Kuwajima, G. Localization and Subcellular Distribution ofN-Copine in Mouse Brain. J. Neurochem. 1999, 72, 373–379. [Google Scholar] [CrossRef]
  331. Zhu, B.; Zha, J.; Long, Y.; Hu, X.; Chen, G.; Wang, X. Increased expression of copine VI in patients with refractory epilepsy and a rat model. J. Neurol. Sci. 2016, 360, 30–36. [Google Scholar] [CrossRef]
  332. Lai, Y.; Hu, X.; Chen, G.-J.; Wang, X.; Zhu, B.-L. Down-regulation of adenylate kinase 5 in temporal lobe epilepsy patients and rat model. J. Neurol. Sci. 2016, 366, 20–26. [Google Scholar] [CrossRef] [PubMed]
  333. Barnum, S.R. Complement: A primer for the coming therapeutic revolution. Pharmacol. Ther. 2017, 172, 63–72. [Google Scholar] [CrossRef] [PubMed]
  334. Ricklin, D.; Hajishengallis, G.; Yang, K.; Lambris, J.D. Complement: A key system for immune surveillance and homeostasis. Nat. Immunol. 2010, 11, 785–797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  335. Kolev, M.; Le Friec, G.; Kemper, C. Complement — tapping into new sites and effector systems. Nat. Rev. Immunol. 2014, 14, 811–820. [Google Scholar] [CrossRef]
  336. Merle, N.S.; Noe, R.; Halbwachs-Mecarelli, L.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement System Part II: Role in Immunity. Front. Immunol. 2015, 6, 257. [Google Scholar] [CrossRef] [Green Version]
  337. Nesargikar, P.; Spiller, B.; Chavez, R. The complement system: History, pathways, cascade and inhibitors. Eur. J. Microbiol. Immunol. 2012, 2, 103–111. [Google Scholar] [CrossRef] [PubMed]
  338. Merle, N.S.; Church, S.E.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement System Part I – Molecular Mechanisms of Activation and Regulation. Front. Immunol. 2015, 6, 262. [Google Scholar] [CrossRef] [Green Version]
  339. Morgan, B.P. Regulation of the complement membrane attack pathway. Crit. Rev. Immunol. 1999, 19, 26. [Google Scholar] [CrossRef]
  340. Bubeck, D. The Making of a Macromolecular Machine: Assembly of the Membrane Attack Complex. Biochemistry 2014, 53, 1908–1915. [Google Scholar] [CrossRef]
  341. Huber-Lang, M.; Younkin, E.M.; Sarma, J.V.; Riedemann, N.; McGuire, S.R.; Lu, K.T.; Kunkel, R.; Younger, J.G.; Zetoune, F.S.; Ward, P.A. Generation of C5a by Phagocytic Cells. Am. J. Pathol. 2002, 161, 1849–1859. [Google Scholar] [CrossRef] [Green Version]
  342. Klos, A.; Tenner, A.J.; Johswich, K.-O.; Ager, R.R.; Reis, E.S.; Köhl, J. The role of the anaphylatoxins in health and disease. Mol. Immunol. 2009, 46, 2753–2766. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  343. Woodruff, T.M.; Ager, R.R.; Tenner, A.J.; Noakes, P.G.; Taylor, S.M. The Role of the Complement System and the Activation Fragment C5a in the Central Nervous System. Neuro Mol. Med. 2009, 12, 179–192. [Google Scholar] [CrossRef] [PubMed]
  344. Gerard, N.P.; Gerard, C. The chemotactic receptor for human C5a anaphylatoxin. Nat. Cell Biol. 1991, 349, 614–617. [Google Scholar] [CrossRef] [PubMed]
  345. Becker, A.J.; Chen, J.; Zien, A.; Sochivko, D.; Normann, S.; Schramm, J.; Elger, C.E.; Wiestler, O.D.; Blümcke, I. Correlated stage- and subfield-associated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy. Eur. J. Neurosci. 2003, 18, 2792–2802. [Google Scholar] [CrossRef] [PubMed]
  346. Jamali, S.; Bartolomei, F.; Robaglia-Schlupp, A.; Massacrier, A.; Peragut, J.-C.; Régis, J.; Dufour, H.; Ravid, R.; Roll, P.; Pereira, S.; et al. Large-scale expression study of human mesial temporal lobe epilepsy: Evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex. Brain 2006, 129, 625–641. [Google Scholar] [CrossRef] [Green Version]
  347. Jamali, S.; Salzmann, A.; Perroud, N.; Ponsole-Lenfant, M.; Cillario, J.; Roll, P.; Roeckel-Trevisiol, N.; Crespel, A.; Balzar, J.; Schlachter, K.; et al. Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures. PLoS ONE 2010, 5, e12740. [Google Scholar] [CrossRef] [Green Version]
  348. Aronica, E.; Boer, K.; Van Vliet, E.A.; Redeker, S.; Baayen, J.C.; Spliet, W.G.; Van Rijen, P.C.; Troost, D.; Da Silva, F.L.; Wadman, W.J.; et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis. 2007, 26, 497–511. [Google Scholar] [CrossRef]
  349. Gorter, J.A.; Van Vliet, E.A.; Aronica, E.; Breit, T.; Rauwerda, H.; Da Silva, F.H.L.; Wadman, W.J. Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy. J. Neurosci. 2006, 26, 11083–11110. [Google Scholar] [CrossRef]
  350. Kharatishvili, I.; Shan, Z.Y.; She, D.; Foong, S.; Kurniawan, N.D.; Reutens, D.C. MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy. Brain Struct. Funct. 2013, 219, 683–706. [Google Scholar] [CrossRef]
  351. Xiong, Z.-Q.; Qian, W.; Suzuki, K.; McNamara, J.O. Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration. J. Neurosci. 2003, 23, 955–960. [Google Scholar] [CrossRef]
  352. Libbey, J.E.; Kirkman, N.J.; Wilcox, K.S.; White, H.S.; Fujinami, R.S. Role for Complement in the Development of Seizures following Acute Viral Infection. J. Virol. 2010, 84, 6452–6460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  353. Holtman, L.; Van Vliet, E.; Baas, F.; Aronica, E.; Gorter, J.A. Complement protein 6 deficiency in PVG/c rats does not lead to neuroprotection against seizure induced cell death. Neuroscience 2011, 188, 109–116. [Google Scholar] [CrossRef] [PubMed]
  354. Benson, M.J.; Manzanero, S.; Borges, K. The effects of C5aR1 on leukocyte infiltration following pilocarpine-induced status epilepticus. Epilepsia 2017, 58, e54–e58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  355. Benson, M.J.; Thomas, N.K.; Talwar, S.; Hodson, M.P.; Lynch, J.W.; Woodruff, T.M.; Borges, K. A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models. Neurobiol. Dis. 2015, 76, 87–97. [Google Scholar] [CrossRef] [PubMed]
  356. Nomaru, H.; Sakumi, K.; Katogi, A.; Ohnishi, Y.N.; Kajitani, K.; Tsuchimoto, D.; Nestler, E.J.; Nakabeppu, Y. Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. Glia 2014, 62, 1284–1298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  357. Wyatt, S.K.; Witt, T.; Barbaro, N.M.; Cohen-Gadol, A.A.; Brewster, A.L. Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp. Neurol. 2017, 295, 184–193. [Google Scholar] [CrossRef] [PubMed]
  358. Schartz, N.D.; Wyatt-Johnson, S.K.; Price, L.R.; Colin, S.A.; Brewster, A.L. Status epilepticus triggers long-lasting activation of complement C1q-C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy. Neurobiol. Dis. 2018, 109, 163–173. [Google Scholar] [CrossRef]
  359. Başaran, N.; Hincal, F.; Kansu, E.; Cidotǧer, A.; Cǧer, A. Humoral and cellular immune parameters in untreated and phenytoin- or carbamazepine-treated epileptic patients. Int. J. Immunopharmacol. 1994, 16, 1071–1077. [Google Scholar] [CrossRef]
  360. Kopczynska, M.; Zelek, W.M.; Vespa, S.; Touchard, S.; Wardle, M.; Loveless, S.; Thomas, R.H.; Hamandi, K.; Morgan, B.P. Complement system biomarkers in epilepsy. Seizure 2018, 60, 1–7. [Google Scholar] [CrossRef] [Green Version]
  361. Hillmen, P.; Young, N.S.; Hubert, S.; Brodsky, R.A.; Socié, G.; Muus, P.; Röth, A.; Szer, J.; Elebute, M.O.; Nakamura, R.; et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N. Engl. J. Med. 2006, 355, 1233–1243. [Google Scholar] [CrossRef]
  362. Hillmen, P.; Muus, P.; Röth, A.; Elebute, M.O.; Risitano, A.M.; Schrezenmeier, H.; Szer, J.; Browne, P.; Maciejewski, J.P.; Schubert, J.; et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 2013, 162, 62–73. [Google Scholar] [CrossRef] [PubMed]
  363. Wong, E.K.; Kavanagh, D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl. Res. 2015, 165, 306–320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  364. Tabrizi, M.A.; Baraldi, P.G.; Baraldi, S.; Gessi, S.; Merighi, S.; Borea, P.A. Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med. Res. Rev. 2016, 37, 936–983. [Google Scholar] [CrossRef] [PubMed]
  365. Tominaga, M.; Caterina, M.J.; Malmberg, A.B.; Rosen, T.A.; Gilbert, H.; Skinner, K.; Raumann, B.E.; Basbaum, A.I.; Julius, D. The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli. Neuron 1998, 21, 531–543. [Google Scholar] [CrossRef] [Green Version]
  366. Zygmunt, P.M.; Petersson, J.; Andersson, D.A.; Chuang, H.-H.; Sørgård, M.; Di Marzo, V.; Julius, D.; Högestätt, E.D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nat. Cell Biol. 1999, 400, 452–457. [Google Scholar] [CrossRef]
  367. Shin, J.; Cho, H.; Hwang, S.W.; Jung, J.; Shin, C.Y.; Lee, S.-Y.; Kim, S.H.; Lee, M.G.; Choi, Y.H.; Kim, J.; et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc. Natl. Acad. Sci. USA 2002, 99, 10150–10155. [Google Scholar] [CrossRef] [Green Version]
  368. Caterina, M.J.; Schumacher, M.A.; Tominaga, M.; Rosen, T.A.; Levine, J.D.; Julius, D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nat. Cell Biol. 1997, 389, 816–824. [Google Scholar] [CrossRef]
  369. Mori, F.; Ribolsi, M.; Kusayanagi, H.; Monteleone, F.; Mantovani, V.; Buttari, F.; Marasco, E.; Bernardi, G.; Maccarrone, M.; Centonze, D. TRPV1 Channels Regulate Cortical Excitability in Humans. J. Neurosci. 2012, 32, 873–879. [Google Scholar] [CrossRef] [Green Version]
  370. Miyake, T.; Shirakawa, H.; Nakagawa, T.; Kaneko, S. Activation of mitochondrial transient receptor potential vanilloid 1 channel contributes to microglial migration. Glia 2015, 63, 1870–1882. [Google Scholar] [CrossRef] [Green Version]
  371. Mezey, É.; Tóth, Z.E.; Cortright, D.N.; Arzubi, M.K.; Krause, J.E.; Elde, R.; Guo, A.; Blumberg, P.M.; Szallasi, A. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. USA 2000, 97, 3655–3660. [Google Scholar] [CrossRef]
  372. Puente, N.; Reguero, L.; Elezgarai, I.; Canduela, M.-J.; Mendizabal-Zubiaga, J.; Ramos, A.; Fernandez-Espejo, E.; Grandes, P. The transient receptor potential vanilloid-1 is localized at excitatory synapses in the mouse dentate gyrus. Brain Struct. Funct. 2014, 220, 1187–1194. [Google Scholar] [CrossRef] [PubMed]
  373. Canduela, M.-J.; Mendizabal-Zubiaga, J.; Puente, N.; Reguero, L.; Elezgarai, I.; Ramos, A.; Gerrikagoitia, I.; Grandes, P. Visualization by High Resolution Immunoelectron Microscopy of the Transient Receptor Potential Vanilloid-1 at Inhibitory Synapses of the Mouse Dentate Gyrus. PLoS ONE 2015, 10, e0119401. [Google Scholar] [CrossRef] [PubMed]
  374. Southall, M.D.; Li, T.; Gharibova, L.S.; Pei, Y.; Nicol, G.D.; Travers, J.B. Activation of Epidermal Vanilloid Receptor-1 Induces Release of Proinflammatory Mediators in Human Keratinocytes. J. Pharmacol. Exp. Ther. 2003, 304, 217–222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  375. Birder, L.A.; Kanai, A.J.; De Groat, W.C.; Kiss, S.; Nealen, M.L.; Burke, N.E.; Dineley, K.E.; Watkins, S.; Reynolds, I.J.; Caterina, M.J. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc. Natl. Acad. Sci. USA 2001, 98, 13396–13401. [Google Scholar] [CrossRef] [Green Version]
  376. Akiba, Y.; Kato, S.; Katsube, K.-I.; Nakamura, M.; Takeuchi, K.; Ishii, H.; Hibi, T. Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet β cells modulates insulin secretion in rats. Biochem. Biophys. Res. Commun. 2004, 321, 219–225. [Google Scholar] [CrossRef]
  377. Heiner, I.; Eisfeld, J.; Halaszovich, C.R.; Wehage, E.M.; Jüngling, E.; Zitt, C.; Lückhoff, A. Expression profile of the transient receptor potential (TRP) family in neutrophil granulocytes: Evidence for currents through long TRP channel 2 induced by ADP-ribose and NAD. Biochem. J. 2003, 371, 1045–1053. [Google Scholar] [CrossRef] [Green Version]
  378. Golech, S.A.; McCarron, R.M.; Chen, Y.; Bembry, J.; Lenz, F.; Mechoulam, R.; Shohami, E.; Spatz, M. Human brain endothelium: Coexpression and function of vanilloid and endocannabinoid receptors. Mol. Brain Res. 2004, 132, 87–92. [Google Scholar] [CrossRef]
  379. Saunders, C.I.; Kunde, D.; Crawford, A.; Geraghty, D.P. Expression of transient receptor potential vanilloid 1 (TRPV1) and 2 (TRPV2) in human peripheral blood. Mol. Immunol. 2007, 44, 1429–1435. [Google Scholar] [CrossRef]
  380. Gibson, H.E.; Edwards, J.G.; Page, R.S.; Van Hook, M.J.; Kauer, J.A. TRPV1 Channels Mediate Long-Term Depression at Synapses on Hippocampal Interneurons. Neuron 2008, 57, 746–759. [Google Scholar] [CrossRef] [Green Version]
  381. Marinelli, S.; Pascucci, T.; Bernardi, G.; Puglisi-Allegra, S.; Mercuri, N.B. Activation of TRPV1 in the VTA Excites Dopaminergic Neurons and Increases Chemical- and Noxious-Induced Dopamine Release in the Nucleus Accumbens. Neuropsychopharmacology 2004, 30, 864–870. [Google Scholar] [CrossRef]
  382. Shoudai, K.; Peters, J.H.; McDougall, S.J.; Fawley, J.A.; Andresen, M.C. Thermally Active TRPV1 Tonically Drives Central Spontaneous Glutamate Release. J. Neurosci. 2010, 30, 14470–14475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  383. Köles, L.; Garção, P.; Zádori, Z.S.; Ferreira, S.G.; Pinheiro, B.S.; Da Silva-Santos, C.S.; Ledent, C.; Köfalvi, A. Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain. Brain Res. Bull. 2013, 97, 126–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  384. Bhaskaran, M.D.; Smith, B.N. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy. Exp. Neurol. 2010, 222, 529–536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  385. Peters, J.H.; McDougall, S.J.; Fawley, J.A.; Smith, S.M.; Andresen, M.C. Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons. Neuron. 2010, 65, 657–669. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  386. Petrovszki, Z.; Adam, G.; Kekesi, G.; Tuboly, G.; Morvay, Z.; Nagy, E.; Benedek, G.; Horvath, G. The effects of juvenile capsaicin desensitization in rats: Behavioral impairments. Physiol. Behav. 2014, 125, 38–44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  387. Muzzi, M.; Felici, R.; Cavone, L.; Gerace, E.; Minassi, A.; Appendino, G.; Moroni, F.; Chiarugi, A. Ischemic Neuroprotection by TRPV1 Receptor-Induced Hypothermia. Br. J. Pharmacol. 2012, 32, 978–982. [Google Scholar] [CrossRef] [Green Version]
  388. Keeble, J.; Russell, F.; Curtis, B.; Starr, A.; Pintér, E.; Brain, S.D. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum. 2005, 52, 3248–3256. [Google Scholar] [CrossRef]
  389. Abdelhamid, R.E.; Kovács, K.J.; Nunez, M.G.; Larson, A.A. Depressive behavior in the forced swim test can be induced by TRPV1 receptor activity and is dependent on NMDA receptors. Pharmacol. Res. 2014, 79, 21–27. [Google Scholar] [CrossRef] [Green Version]
  390. Marsch, R.; Foeller, E.; Rammes, G.; Bunck, M.; Kössl, M.; Holsboer, F.; Zieglgänsberger, W.; Landgraf, R.; Lutz, B.; Wotjak, C.T. Reduced Anxiety, Conditioned Fear, and Hippocampal Long-Term Potentiation in Transient Receptor Potential Vanilloid Type 1 Receptor-Deficient Mice. J. Neurosci. 2007, 27, 832–839. [Google Scholar] [CrossRef]
  391. Razavinasab, M.; Shamsizadeh, A.; Shabani, M.; Nazeri, M.; Allahtavakoli, M.; Asadi-Shekaari, M.; Esmaeili-Mahani, S.; Sheibani, V. Pharmacological blockade of TRPV1 receptors modulates the effects of 6-OHDA on motor and cognitive functions in a rat model of Parkinson’s disease. Fundam. Clin. Pharmacol. 2012, 27, 632–640. [Google Scholar] [CrossRef]
  392. Nazıroğlu, M. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy. Curr. Neuropharmacol. 2015, 13, 239–247. [Google Scholar] [CrossRef] [Green Version]
  393. Huang, W.-X.; Yu-Qiang, L.; Sanchez, R.M.; Liu, Y.-Q.; Min, J.-W.; Hu, J.-J.; Bsoul, N.B.; Han, S.; Yin, J.; Liu, W.-H.; et al. TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain. Brain Behav. Immun. 2015, 48, 68–77. [Google Scholar] [CrossRef]
  394. Kong, W.-L.; Min, J.-W.; Liu, Y.-L.; Li, J.-X.; He, X.-H.; Peng, B. Role of TRPV1 in susceptibility to PTZ-induced seizure following repeated hyperthermia challenges in neonatal mice. Epilepsy Behav. 2014, 31, 276–280. [Google Scholar] [CrossRef]
  395. Gonzalez-Reyes, L.E.; Ladas, T.P.; Chiang, C.-C.; Durand, D.M. TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo. Exp. Neurol. 2013, 250, 321–332. [Google Scholar] [CrossRef] [Green Version]
  396. Cho, S.J.; Vaca, M.A.; Miranda, C.J.; N’Gouemo, P. Inhibition of transient potential receptor vanilloid type 1 suppresses seizure susceptibility in the genetically epilepsy-prone rat. CNS Neurosci. Ther. 2017, 24, 18–28. [Google Scholar] [CrossRef]
  397. Manna, S.S.; Umathe, S.N. Involvement of transient receptor potential vanilloid type 1 channels in the pro-convulsant effect of anandamide in pentylenetetrazole-induced seizures. Epilepsy Res. 2012, 100, 113–124. [Google Scholar] [CrossRef] [PubMed]
  398. Socała, K.; Nieoczym, D.; Pieróg, M.; Wlaź, P. α-Spinasterol, a TRPV1 receptor antagonist, elevates the seizure threshold in three acute seizure tests in mice. J. Neural Transm. 2015, 122, 1239–1247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  399. Jia, Y.-F.; Li, Y.-C.; Tang, Y.-P.; Cao, J.; Wang, L.-P.; Yang, Y.-X.; Xu, L.; Mao, R.-R. Interference of TRPV1 function altered the susceptibility of PTZ-induced seizures. Front. Cell. Neurosci. 2015, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  400. Nazıroğlu, M.; Taner, A.N.; Balbay, E.; Çiğ, B. Inhibitions of anandamide transport and FAAH synthesis decrease apoptosis and oxidative stress through inhibition of TRPV1 channel in an in vitro seizure model. Mol. Cell. Biochem. 2019, 453, 143–155. [Google Scholar] [CrossRef]
  401. Saffarzadeh, F.; Eslamizade, M.J.; Ghadiri, T.; Mousavi, S.M.M.; Hadjighassem, M.; Gorji, A. Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain. Synapse 2015, 69, 375–383. [Google Scholar] [CrossRef]
  402. Saffarzadeh, F.; Eslamizade, M.; Mousavi, S.; Abraki, S.; Hadjighassem, M.; Gorji, A. TRPV1 receptors augment basal synaptic transmission in CA1 and CA3 pyramidal neurons in epilepsy. Neuroscience 2016, 314, 170–178. [Google Scholar] [CrossRef]
  403. Shirazi, M.; Izadi, M.; Amin, M.; Rezvani, M.E.; Roohbakhsh, A.; Shamsizadeh, A. Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats. Neurol. Sci. 2014, 35, 1235–1241. [Google Scholar] [CrossRef]
  404. Sun, F.-J.; Guo, W.; Zheng, D.-H.; Zhang, C.-Q.; Li, S.; Liu, S.-Y.; Yin, Q.; Yang, H.; Shu, H.-F. Increased Expression of TRPV1 in the Cortex and Hippocampus from Patients with Mesial Temporal Lobe Epilepsy. J. Mol. Neurosci. 2012, 49, 182–193. [Google Scholar] [CrossRef] [PubMed]
  405. Vrontakis, M.E. Galanin: A Biologically Active Peptide. Curr. Drug Target -CNS Neurol. Disord. 2002, 1, 531–541. [Google Scholar] [CrossRef]
  406. Langel, Ü.; Bartfai, T. Chemistry and molecular biology of galanin receptor ligands. Ann. N. Y. Acad. Sci. 1998, 863, 86–93. [Google Scholar] [CrossRef] [PubMed]
  407. Vrontakis, M.E.; Yamamoto, T.; Schroedter, I.C.; Nagy, J.I.; Friesen, H.G. Estrogen induction of galanin synthesis in the rat anterior pituitary gland demonstrated by in situ hybridization and immunohistochemistry. Neurosci. Lett. 1989, 100, 59–64. [Google Scholar] [CrossRef]
  408. Mohney, R.P.; Zigmond, R.E. Galanin expression is decreased by cAMP-elevating agents in cultured sympathetic ganglia. Neuro Rep. 1999, 10, 1221–1224. [Google Scholar] [CrossRef]
  409. Hooi, S.C.; Koenig, J.I.; Abraczinskas, D.R.; Kaplan, L.M. Regulation of anterior pituitary galanin gene expression by thyroid hormone. Mol. Brain Res. 1997, 51, 15–22. [Google Scholar] [CrossRef]
  410. Brann, D.W.; Chorich, L.P.; Mahesh, V.B. Effect of Progesterone on Galanin mRNA Levels in the Hypothalamus and the Pituitary: Correlation with the Gonadotropin Surge. Neuroendocrinology 1993, 58, 531–538. [Google Scholar] [CrossRef]
  411. Corness, J.; Stevens, B.; Fields, R.D.; Hökfelt, T. NGF and LIF both regulate galanin gene expression in primary DRG cultures. Neuroreport 1998, 9, 1533–1536. [Google Scholar] [CrossRef]
  412. Lang, R.; Gundlach, A.L.; Holmes, F.E.; Hobson, S.A.; Wynick, D.; Hökfelt, T.; Kofler, B. Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity. Pharmacol. Rev. 2014, 67, 118–175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  413. Melander, T.; Hökfelt, T.; Rökaeus, A.; Cuello, A.C.; Oertel, W.H.; Verhofstad, A.; Goldstein, M. Coexistence of galanin-like immunoreactivity with catecholamines, 5- hydroxytryptamine, GABA and neuropeptides in the rat CNS. J. Neurosci. 1986, 6, 3640–3654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  414. Zhang, X.; Nicholas, A.; Ho¨kfelt, T. Ultrastructural studies on peptides in the dorsal horn of the spinal cord—I. Co-existence of galanin with other peptides in primary afferents in normal rats. Neuroscience 1993, 57, 365–384. [Google Scholar] [CrossRef]
  415. Crawley, J. The role of galanin in feeding behavior. Neuropeptides 1999, 33, 369–375. [Google Scholar] [CrossRef]
  416. Liu, H.-X.; Hökfelt, T. The participation of galanin in pain processing at the spinal level. Trends Pharmacol. Sci. 2002, 23, 468–474. [Google Scholar] [CrossRef]
  417. Xu, X.-F.; Zhang, D.-D.; Liao, J.-C.; Xiao, L.; Wang, Q.; Qiu, W. Galanin and its receptor system promote the repair of injured sciatic nerves in diabetic rats. Neural Regen. Res. 2016, 11, 1517–1526. [Google Scholar] [CrossRef]
  418. Steininger, T.L.; Gong, H.; McGinty, D.; Szymusiak, R. Subregional organization of preoptic area /anterior hypothalamic projections to arousal-related monoaminergic cell groups. J. Comp. Neurol. 2001, 429, 638–653. [Google Scholar] [CrossRef]
  419. Fraley, G.; Thomas-Smith, S.; Acohido, B.; Steiner, R.; Clifton, D. Stimulation of sexual behavior in the male rat by galanin-like peptide. Horm. Behav. 2004, 46, 551–557. [Google Scholar] [CrossRef] [Green Version]
  420. Ögren, S.O.; Schött, P.A.; Kehr, J.; Misane, I.; Razani, H. Galanin and learning. Brain Res. 1999, 848, 174–182. [Google Scholar] [CrossRef]
  421. Ögren, S.O.; Kuteeva, E.; Elvander-Tottie, E.; Hökfelt, T. Neuropeptides in learning and memory processes with focus on galanin. Eur. J. Pharmacol. 2010, 626, 9–17. [Google Scholar] [CrossRef]
  422. Bartfai, T.; Hökfelt, T.; Langel, U. Galanin--a neuroendocrine peptide. Crit. Rev. Neurobiol. 1993, 7, 229–274. [Google Scholar]
  423. Bauer, F.; Zintel, A.; Kenny, M.; Calder, D.; Ghatei, M.; Bloom, S. Inhibitory effect of galanin on postprandial gastrointestinal motility and gut hormone release in humans. Gastroenterol. 1989, 97, 260–264. [Google Scholar] [CrossRef]
  424. Holm, L.; Hilke, S.; Ádori, C.; Theodorsson, E.; Hökfelt, T.; Theodorsson, A. Changes in galanin and GalR1 gene expression in discrete brain regions after transient occlusion of the middle cerebral artery in female rats. Neuropeptides 2012, 46, 19–27. [Google Scholar] [CrossRef] [PubMed]
  425. Holmes, P.V.; Blanchard, D.; Blanchard, R.J.; Brady, L.S.; Crawley, J.N. Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus. Pharmacol. Biochem. Behav. 1995, 50, 655–660. [Google Scholar] [CrossRef]
  426. Flatters, S.J.; Fox, A.J.; Dickenson, A.H. Nerve injury induces plasticity that results in spinal inhibitory effects of galanin. Pain 2002, 98, 249–258. [Google Scholar] [CrossRef]
  427. Wraith, D.C.; Pope, R.; Butzkueven, H.; Holder, H.; Vanderplank, P.; Lowrey, P.; Day, M.J.; Gundlach, A.L.; Kilpatrick, T.J.; Scolding, N.J.; et al. A role for galanin in human and experimental inflammatory demyelination. Proc. Natl. Acad. Sci. USA 2009, 106, 15466–15471. [Google Scholar] [CrossRef] [Green Version]
  428. Baraka, A.; ElGhotny, S. Study of the effect of inhibiting galanin in Alzheimer’s disease induced in rats. Eur. J. Pharmacol. 2010, 641, 123–127. [Google Scholar] [CrossRef]
  429. Branchek, T.A.; Smith, K.E.; Gerald, C.; Walker, M.W. Galanin receptor subtypes. Trends Pharmacol. Sci. 2000, 21, 109–117. [Google Scholar] [CrossRef]
  430. Skofitsch, G.; Sills, M.A.; Jacobowitz, D.M. Autoradiographic distribution of 125I-galanin binding sites in the rat central nervous system. Peptides 1986, 7, 1029–1042. [Google Scholar] [CrossRef]
  431. Melander, T.; Hökfelt, T.; Rökaeus, A. Distribution of galaninlike immunoreactivity in the rat central nervous system. J. Comp. Neurol. 1986, 248, 475–517. [Google Scholar] [CrossRef]
  432. Nicholl, J.; Kofler, B.; Sutherland, G.; Shine, J.; Iismaa, T. Assignment of the Gene Encoding Human Galanin Receptor (GALNR) to 18q23 by in Situ Hybridization. Genomics 1995, 30, 629–630. [Google Scholar] [CrossRef]
  433. Zini, S.; Roisin, M.-P.; Armengaud, C.; Ben-Ari, Y. Effect of potassium channel modulators on the release of glutamate induced by ischaemic-like conditions in rat hippocampal slices. Neurosci. Lett. 1993, 153, 202–205. [Google Scholar] [CrossRef]
  434. Zini, S.; Roisin, M.-P.; Langel, Ü.; Bartfai, T.; Ben-Ari, Y. Galanin reduces release of endogeneous excitatory amino acids in the rat hippocampus. Eur. J. Pharmacol. Mol. Pharmacol. 1993, 245, 1–7. [Google Scholar] [CrossRef]
  435. Endoh, T.; Sato, D.; Wada, Y.; Shibukawa, Y.; Ishihara, K.; Hashimoto, S.; Yoshinari, M.; Matsuzaka, K.; Tazaki, M.; Inoue, T. Galanin inhibits calcium channels via Gαi-protein mediated by GalR1 in rat nucleus tractus solitarius. Brain Res. 2008, 1229, 37–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  436. Badie-Mahdavi, H.; Lu, X.; Behrens, M.; Bartfai, T. Role of galanin receptor 1 and galanin receptor 2 activation in synaptic plasticity associated with 3′,5′-cyclic AMP response element-binding protein phosphorylation in the dentate gyrus: Studies with a galanin receptor 2 agonist and galanin receptor 1 knockout mice. Neuroscience 2005, 133, 591–604. [Google Scholar] [CrossRef]
  437. Blackshear, A.; Yamamoto, M.; Anderson, B.J.; Holmes, P.V.; Lundström, L.; Langel, Ü.; Robinson, J.K. Intracerebroventricular administration of galanin or galanin receptor subtype 1 agonist M617 induces c-Fos activation in central amygdala and dorsomedial hypothalamus. Peptides 2007, 28, 1120–1124. [Google Scholar] [CrossRef] [PubMed]
  438. Chen, Y.; Laburthe, M.; Amiranoff, B. Galanin inhibits adenylate cyclase of rat brain membranes. Peptides 1992, 13, 339–341. [Google Scholar] [CrossRef]
  439. Wang, S.; Hashemi, T.; Fried, S.; Clemmons, A.L.; Hawes, B.E. Differential Intracellular Signaling of the GalR1 and GalR2 Galanin Receptor Subtypes. Biochemistry 1998, 37, 6711–6717. [Google Scholar] [CrossRef]
  440. Takigawa, T.; Alzheimer, C. G protein-activated inwardly rectifying K+ (GIRK) currents in dendrites of rat neocortical pyramidal cells. J. Physiol. 1999, 517, 385–390. [Google Scholar] [CrossRef]
  441. Fathi, Z.; Battaglino, P.M.; Iben, L.G.; Li, H.; Baker, E.; Zhang, D.; McGovern, R.; Mahle, C.D.; Sutherland, G.R.; Iismaa, T.P.; et al. Molecular characterization, pharmacological properties and chromosomal localization of the human GALR2 galanin receptor. Mol. Brain Res. 1998, 58, 156–169. [Google Scholar] [CrossRef]
  442. Seufferlein, T.; Rozengurt, E. Galanin, neurotensin, and phorbol esters rapidly stimulate activation of mitogen-activated protein kinase in small cell lung cancer cells. Cancer Res. 1996, 56, 5758–5764. [Google Scholar] [PubMed]
  443. Hawes, J.J.; Narasimhaiah, R.; Picciotto, M.R. Galanin and galanin-like peptide modulate neurite outgrowth via protein kinase C-mediated activation of extracellular signal-related kinase. Eur. J. Neurosci. 2006, 23, 2937–2946. [Google Scholar] [CrossRef]
  444. Ifuku, M.; Okuno, Y.; Yamakawa, Y.; Izumi, K.; Seifert, S.; Kettenmann, H.; Noda, M. Functional importance of inositol-1,4,5-triphosphate-induced intracellular Ca2+ mobilization in galanin-induced microglial migration. J. Neurochem. 2011, 117, 61–70. [Google Scholar] [CrossRef]
  445. Kolakowski, L.F., Jr.; O’Neill, G.P.; Howard, A.D.; Broussard, S.R.; Sullivan, K.A.; Feighner, S.D.; Sawzdargo, M.; Nguyen, T.; Kargman, S.; Shiao, L.-L.; et al. Molecular Characterization and Expression of Cloned Human Galanin Receptors GALR2 and GALR3. J. Neurochem. 2002, 71, 2239–2251. [Google Scholar] [CrossRef] [PubMed]
  446. Mansouri, S.; Barde, S.; Ortsäter, H.; Eweida, M.; Darsalia, V.; Langel, Ü.; Sjöholm, Å.; Hökfelt, T.; Patrone, C. GalR3 activation promotes adult neural stem cell survival in response to a diabeticmilieu. J. Neurochem. 2013, 127, 209–220. [Google Scholar] [CrossRef] [PubMed]
  447. Smith, K.E.; Walker, M.W.; Artymyshyn, R.; A Bard, J.; Borowsky, B.; Tamm, J.A.; Yao, W.-J.; Vaysse, P.J.-J.; Branchek, T.A.; Gerald, C.; et al. Cloned Human and Rat Galanin GALR3 Receptors. J. Biol. Chem. 1998, 273, 23321–23326. [Google Scholar] [CrossRef] [Green Version]
  448. Mennicken, F.; Hoffert, C.; Pelletier, M.; Ahmad, S.; O’Donnell, D. Restricted distribution of galanin receptor 3 (GalR3) mRNA in the adult rat central nervous system. J. Chem. Neuroanat. 2002, 24, 257–268. [Google Scholar] [CrossRef]
  449. Mazarati, A.; Langel, Ü.; Bartfai, T. Book Review: Galanin: An Endogenous Anticonvulsant? Neuroscience 2001, 7, 506–517. [Google Scholar] [CrossRef]
  450. Mazarati, A.; Liu, H.; Soomets, U.; Sankar, R.; Shin, D.; Katsumori, H.; Langel, Ü.; Wasterlain, C.G. Galanin Modulation of Seizures and Seizure Modulation of Hippocampal Galanin in Animal Models of Status Epilepticus. J. Neurosci. 1998, 18, 10070–10077. [Google Scholar] [CrossRef]
  451. Wilson, D.N.; Chung, H.; Elliott, R.C.; Bremer, E.; George, D.; Koh, S. Microarray Analysis of Postictal Transcriptional Regulation of Neuropeptides. J. Mol. Neurosci. 2005, 25, 285–298. [Google Scholar] [CrossRef]
  452. Mazarati, A.M.; Halászi, E.; Telegdy, G. Anticonvulsive effects of galanin administered into the central nervous system upon the picrotoxin-kindled seizure syndrome in rats. Brain Res. 1992, 589, 164–166. [Google Scholar] [CrossRef]
  453. Ledri, M.; Sørensen, A.T.; Madsen, M.G.; Christiansen, S.H.; Ledri, L.N.; Cifra, A.; Bengzon, J.; Hellström-Lindberg, E.; Pinborg, L.H.; Jespersen, B.; et al. Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus. J. Neurosci. 2015, 35, 9622–9631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  454. Guipponi, M.; Chentouf, A.; Webling, K.E.; Freimann, K.; Crespel, A.; Nobile, C.; Lemke, J.R.; Hansen, J.; Dorn, T.; Lesca, G.; et al. Galanin pathogenic mutations in temporal lobe epilepsy. Hum. Mol. Genet. 2015, 24, 3082–3091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  455. Mazarati, A.; Lu, X.; Shinmei, S.; Badie-Mahdavi, H.; Bartfai, T. Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice. Neuroscience 2004, 128, 431–441. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  456. Jacoby, A.S.; Hort, Y.J.; Constantinescu, G.; Shine, J.; Iismaa, T.P. Critical role for GALR1 galanin receptor in galanin regulation of neuroendocrine function and seizure activity. Mol. Brain Res. 2002, 107, 195–200. [Google Scholar] [CrossRef]
  457. Fetissov, S.O.; Jacoby, A.S.; Brumovsky, P.R.; Shine, J.; Iismaa, T.P.; Hökfelt, T. Altered Hippocampal Expression of Neuropeptides in Seizure-prone GALR1 Knockout Mice. Epilepsia 2003, 44, 1022–1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  458. Gottsch, M.L.; Zeng, H.; Hohmann, J.G.; Weinshenker, D.; Clifton, D.K.; Steiner, R.A. Phenotypic Analysis of Mice Deficient in the Type 2 Galanin Receptor (GALR2). Mol. Cell. Biol. 2005, 25, 4804–4811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  459. Mazarati, A.; Lu, X.; Kilk, K.; Langel, Ü.; Wasterlain, C.; Bartfai, T. Galanin type 2 receptors regulate neuronal survival, susceptibility to seizures and seizure-induced neurogenesis in the dentate gyrus. Eur. J. Neurosci. 2004, 19, 3235–3244. [Google Scholar] [CrossRef]
  460. McColl, C.D.; Jacoby, A.S.; Shine, J.; Iismaa, T.P.; Bekkers, J.M. Galanin receptor-1 knockout mice exhibit spontaneous epilepsy, abnormal EEGs and altered inhibition in the hippocampus. Neuropharmacology 2006, 50, 209–218. [Google Scholar] [CrossRef]
  461. Mazarati, A.; Lundström, L.; Sollenberg, U.; Shin, D.; Langel, Ü.; Sankar, R. Regulation of Kindling Epileptogenesis by Hippocampal Galanin Type 1 and Type 2 Receptors: The Effects of Subtype-Selective Agonists and the Role of G-Protein-Mediated Signaling. J. Pharmacol. Exp. Ther. 2006, 318, 700–708. [Google Scholar] [CrossRef] [Green Version]
  462. Bartfai, T.; Lu, X.; Badie-Mahdavi, H.; Barr, A.M.; Mazarati, A.; Hua, X.-Y.; Yaksh, T.; Haberhauer, G.; Ceide, S.C.; Trembleau, L.; et al. Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests. Proc. Natl. Acad. Sci. USA 2004, 101, 10470–10475. [Google Scholar] [CrossRef] [Green Version]
  463. Bulaj, G.; Green, B.R.; Lee, H.-K.; Robertson, C.R.; White, K.; Zhang, L.; Sochanska, M.; Flynn, S.P.; Scholl, E.A.; Pruess, T.H.; et al. Design, Synthesis, and Characterization of High-Affinity, Systemically-Active Galanin Analogues with Potent Anticonvulsant Activities. J. Med. Chem. 2008, 51, 8038–8047. [Google Scholar] [CrossRef]
  464. White, H.S.; Scholl, E.A.; Klein, B.D.; Flynn, S.P.; Pruess, T.H.; Green, B.R.; Zhang, L.; Bulaj, G. Developing novel antiepileptic drugs: Characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models. Neurotherapeutics 2009, 6, 372–380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  465. Walls, A.B.; Flynn, S.P.; West, P.J.; Müller, M.S.; Bak, L.K.; Bulaj, G.; Schousboe, A.; White, H.S. The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission. Epilepsy Res. 2016, 121, 55–63. [Google Scholar] [CrossRef] [PubMed]
  466. Saar, K.; Mazarati, A.M.; Mahlapuu, R.; Hallnemo, G.; Soomets, U.; Kilk, K.; Hellberg, S.; Pooga, M.; Tolf, B.-R.; Shi, T.S.; et al. Anticonvulsant activity of a nonpeptide galanin receptor agonist. Proc. Natl. Acad. Sci. USA 2002, 99, 7136–7141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  467. Metcalf, C.S.; Klein, B.D.; McDougle, D.R.; Zhang, L.; Kaufmann, D.; Bulaj, G.; White, H.S. Preclinical evaluation of intravenous NAX 810-2, a novel GalR2-preferring analog, for anticonvulsant efficacy and pharmacokinetics. Epilepsia 2017, 58, 239–246. [Google Scholar] [CrossRef] [Green Version]
  468. Lu, X.; Roberts, E.; Xia, F.; Sanchez-Alavez, M.; Liu, T.; Baldwin, R.; Wu, S.; Chang, J.; Wasterlain, C.G.; Bartfai, T. GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models. Proc. Natl. Acad. Sci. USA 2010, 107, 15229–15234. [Google Scholar] [CrossRef] [Green Version]
  469. Kokaia, M.; Holmberg, K.; Nanobashvili, A.; Xu, Z.-Q.D.; Kokaia, Z.; Lendahl, U.; Hilke, S.; Theodorsson, E.; Kahl, U.; Bartfai, T.; et al. Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin. Proc. Natl. Acad. Sci. USA 2001, 98, 14006–14011. [Google Scholar] [CrossRef] [Green Version]
  470. Schlifke, I.; Kuteeva, E.; Hökfelt, T.; Kokaia, M. Galanin expressed in the excitatory fibers attenuates synaptic strength and generalized seizures in the piriform cortex of mice. Exp. Neurol. 2006, 200, 398–406. [Google Scholar] [CrossRef] [Green Version]
  471. Kanter-Schlifke, I.; Sørensen, A.T.; Ledri, M.; Kuteeva, E.; Hokfelt, T.; Kokaia, M. Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity. Neuroscience 2007, 150, 984–992. [Google Scholar] [CrossRef]
  472. McCown, T.J. Adeno-associated Virus-Mediated Expression and Constitutive Secretion of Galanin Suppresses Limbic Seizure Activity in Vivo. Mol. Ther. 2006, 14, 63–68. [Google Scholar] [CrossRef] [PubMed]
  473. McCown, T.J. Adeno-associated virus vector-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity. Neurotherapeutics 2009, 6, 307–311. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  474. Gray, S.J.; Blake, B.L.; Criswell, H.E.; Nicolson, S.C.; Samulski, R.J.; McCown, T.J. Directed Evolution of a Novel Adeno-associated Virus (AAV) Vector That Crosses the Seizure-compromised Blood–Brain Barrier (BBB). Mol. Ther. 2010, 18, 570–578. [Google Scholar] [CrossRef] [PubMed]
  475. Brzezinski, A. Melatonin in Humans. N. Engl. J. Med. 1997, 336, 186–195. [Google Scholar] [CrossRef]
  476. Axelrod, J.; Weissbach, H. Enzymatic O-Methylation of N-Acetylserotonin to Melatonin. Science 1960, 131, 1312. [Google Scholar] [CrossRef] [PubMed]
  477. Buijs, R.; Hermes, M.H.; Kalsbeek, A. The suprachiasmatic nucleus—paraventricular nucleus interactions: A bridge to the neuroendocrine and autonomic nervous system. Prog. Brain Res. 1999, 119, 365–382. [Google Scholar] [CrossRef]
  478. Cardinali, D.P.; Rosner, J.M. Retinal Localization of the Hydroxyindole-O-methyl Transferase (HIOMT) in the Rat. Endocrinology 1971, 89, 301–303. [Google Scholar] [CrossRef]
  479. Slominski, A.T.; Pisarchik, A.; Semak, I.; Sweatman, T.; Wortsman, J.; Szczesniewski, A.; Slugocki, G.; McNulty, J.; Kauser, S.; Tobin, D.J.; et al. Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J. 2002, 16, 896–898. [Google Scholar] [CrossRef] [Green Version]
  480. Bubenik, G.A. REVIEW: Gastrointestinal Melatonin: Localization, Function, and Clinical Relevance. Dig. Dis. Sci. 2002, 47, 2336–2348. [Google Scholar] [CrossRef]
  481. Conti, A.; Conconi, S.; Hertens, E.; Skwarlo-Sonta, K.; Markowska, M.; Maestroni, G.J. Evidence for melatonin synthesis in mouse and human bone marrow cells. J. Pineal Res. 2000, 28, 193–202. [Google Scholar] [CrossRef]
  482. Carrillo-Vico, A.; Calvo, J.R.; Abreu, P.; Lardone, P.J.; García-Mauriño, S.; Reiter, R.J.; Guerrero, J.M. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: Possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 2004, 18, 537–539. [Google Scholar] [CrossRef] [PubMed]
  483. Zisapel, N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br. J. Pharmacol. 2018, 175, 3190–3199. [Google Scholar] [CrossRef] [PubMed]
  484. Dijk, D.-J.; Cajochen, C. Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J. Biol. Rhythm. 1997, 12, 627–635. [Google Scholar] [CrossRef] [PubMed]
  485. Talpur, H.; Chandio, I.; Brohi, R.; Worku, T.; Rehman, Z.; Bhattarai, D.; Ullah, F.; Jiajia, L.; Yang, L. Research progress on the role of melatonin and its receptors in animal reproduction: A comprehensive review. Reprod. Domest. Anim. 2018, 53, 831–849. [Google Scholar] [CrossRef] [PubMed]
  486. Lo, C.-C.; Lin, S.-H.; Chang, J.-S.; Chien, Y.-W. Effects of Melatonin on Glucose Homeostasis, Antioxidant Ability, and Adipokine Secretion in ICR Mice with NA/STZ-Induced Hyperglycemia. Nutrients 2017, 9, 1187. [Google Scholar] [CrossRef] [Green Version]
  487. Gorfine, T.; Zisapel, N. Melatonin and the human hippocampus, a time dependant interplay. J. Pineal Res. 2007, 43, 80–86. [Google Scholar] [CrossRef]
  488. Baker, J.; Kimpinski, K. Role of melatonin in blood pressure regulation: An adjunct anti-hypertensive agent. Clin. Exp. Pharmacol. Physiol. 2018, 45, 755–766. [Google Scholar] [CrossRef]
  489. Srinivasan, V.; Maestroni, G.J.M.; Cardinali, D.P.; Esquifino, A.I.; Pandi-Perumal, S.R.; Miller, S.C. Melatonin, immune function and aging. Immun. Ageing 2005, 2, 17. [Google Scholar] [CrossRef] [Green Version]
  490. Tan, D.-X.; Manchester, L.C.; Esteban-Zubero, E.; Zhou, Z.; Reiter, R.J. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism. Molcules 2015, 20, 18886–18906. [Google Scholar] [CrossRef] [Green Version]
  491. Andersen, L.P.H. The analgesic effects of exogenous melatonin in humans. Acta Anaesthesiol. Scand. 2016, 60, 1024–1025. [Google Scholar] [CrossRef]
  492. Hansen, M.; Danielsen, A.K.; Hageman, I.; Rosenberg, J.; Gögenur, I. The therapeutic or prophylactic effect of exogenous melatonin against depression and depressive symptoms: A systematic review and meta-analysis. Eur. Neuropsychopharmacol. 2014, 24, 1719–1728. [Google Scholar] [CrossRef] [PubMed]
  493. Hardeland, R. Antioxidative Protection by Melatonin: Multiplicity of Mechanisms from Radical Detoxification to Radical Avoidance. Endocrine 2005, 27, 119–130. [Google Scholar] [CrossRef]
  494. Huang, F.; Yang, Z.; Li, C.-Q. The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear. Vitam. Horm. 2017, 103, 281–294. [Google Scholar] [CrossRef] [PubMed]
  495. Dubocovich, M.L.; Markowska, M. Functional MT1 and MT2 Melatonin Receptors in Mammals. Endocrine 2005, 27, 101–110. [Google Scholar] [CrossRef]
  496. Slaugenhaupt, S.A.; Roca, A.L.; Liebert, C.B.; Altherr, M.R.; Gusella, J.F.; Reppert, S.M. Mapping of the Gene for the Mel1a-Melatonin Receptor to Human Chromosome 4 (MTNR1A) and Mouse Chromosome 8 (Mtnr1a). Genomics 1995, 27, 355–357. [Google Scholar] [CrossRef]
  497. Brydon, L.; Roka, F.; Petit, L.; De Coppet, P.; Tissot, M.; Barrett, P.; Morgan, P.J.; Nanoff, C.; Strosberg, A.D.; Jockers, R. Dual Signaling of Human Mel1a Melatonin Receptors via Gi2, Gi3, and Gq/11 Proteins. Mol. Endocrinol. 1999, 13, 2025–2038. [Google Scholar] [CrossRef]
  498. Liu, J.; Clough, S.J.; Hutchinson, A.J.; Adamah-Biassi, E.B.; Popovska-Gorevski, M.; Dubocovich, M.L. MT1and MT2Melatonin Receptors: A Therapeutic Perspective. Annu. Rev. Pharmacol. Toxicol. 2016, 56, 361–383. [Google Scholar] [CrossRef] [Green Version]
  499. Reppert, S.M.; Godson, C.; Mahle, C.D.; Weaver, D.R.; Slaugenhaupt, S.A.; Gusella, J.F. Molecular characterization of a second melatonin receptor expressed in human retina and brain: The Mel1b melatonin receptor. Proc. Natl. Acad. Sci. USA 1995, 92, 8734–8738. [Google Scholar] [CrossRef] [Green Version]
  500. MacKenzie, R.S.; Melan, M.A.; Passey, D.K.; Witt-Enderby, P.A. Dual coupling of MT1 and MT2 melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascades and their regulation following melatonin exposure. Biochem. Pharmacol. 2002, 63, 587–595. [Google Scholar] [CrossRef]
  501. Nosjean, O.; Ferro, M.; Cogé, F.; Beauverger, P.; Henlin, J.-M.; Lefoulon, F.; Fauchère, J.-L.; Delagrange, P.; Canet, E.; Boutin, J.A. Identification of the Melatonin-binding SiteMT3as the Quinone Reductase 2. J. Biol. Chem. 2000, 275, 31311–31317. [Google Scholar] [CrossRef] [Green Version]
  502. Acufla-Castroviejo, D.; Escames, G.; Macks, M.; Hoyos, A.M.; Carballo, A.M.; Arauzo, M.; Montes, R.; Vives, F. Minireview: Cell protective role of melatonin in the brain. J. Pineal Res. 1995, 19, 57–63. [Google Scholar] [CrossRef]
  503. Nilcs, L.P.; Pickering, D.S.; Arciszewski, M.A. Effects of chronic melatonin administration on GABA and diazepam binding in rat brain. J. Neural Transm. 1987, 70, 117–124. [Google Scholar] [CrossRef] [PubMed]
  504. León, J.; Macías, M.; Escames, G.; Camacho, E.; Khaldy, H.; Martín, M.; Espinosa, A.; Gallo, M.A.; Acuña-Castroviejo, D. Structure-Related Inhibition of Calmodulin-Dependent Neuronal Nitric-Oxide Synthase Activity by Melatonin and Synthetic Kynurenines. Mol. Pharmacol. 2000, 58, 967–975. [Google Scholar] [CrossRef]
  505. Hamdi, A. Melatonin administration increases the affinity of D2 dopamine receptors in the rat striatum. Life Sci. 1998, 63, 2115–2120. [Google Scholar] [CrossRef]
  506. Esposito, S.; Laino, D.; D’Alonzo, R.; Mencarelli, A.; Di Genova, L.; Fattorusso, A.; Argentiero, A.; Mencaroni, E. Pediatric sleep disturbances and treatment with melatonin. J. Transl. Med. 2019, 17, 77. [Google Scholar] [CrossRef] [PubMed]
  507. Barchas, J.; Dacosta, F.; Spector, S. Acute Pharmacology of Melatonin. Nat. Cell Biol. 1967, 214, 919–920. [Google Scholar] [CrossRef]
  508. Fauteck, J.-D.; Böckmann, J.; Wittkowski, W.; Straub, H.; Speckmann, E.-J.; Tuxhorn, I.; Wolf, P.; Pannek, H.; Oppel, F. Melatonin reduces low-Mg2+ epileptiform activity in human temporal slices. Exp. Brain Res. 1995, 107, 321–325. [Google Scholar] [CrossRef]
  509. Borowicz, K.K.; Kamiński, R.; Gasior, M.; Kleinrok, Z.; Czuczwar, S.J. Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice. Eur. Neuropsychopharmacol. 1999, 9, 185–190. [Google Scholar] [CrossRef]
  510. Mevissen, M.; Ebert, U. Anticonvulsant effects of melatonin in amygdala-kindled rats. Neurosci. Lett. 1998, 257, 13–16. [Google Scholar] [CrossRef]
  511. Yildirim, M.; Marangoz, C. Anticonvulsant effects of melatonin on penicillin-induced epileptiform activity in rats. Brain Res. 2006, 1099, 183–188. [Google Scholar] [CrossRef]
  512. Aydin, L.; Gundogan, N.U.; Yazici, C. Anticonvulsant efficacy of melatonin in an experimental model of hyperthermic febrile seizures. Epilepsy Res. 2015, 118, 49–54. [Google Scholar] [CrossRef] [PubMed]
  513. Costa-Lotufo, L.V.; Fonteles, M.M.D.F.; Lima, I.S.P.; De Oliveira, A.A.; Nascimento, V.S.; De Bruin, V.M.; Viana, G.S. Attenuating effects of melatonin on pilocarpine-induced seizures in rats. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 2002, 131, 521–529. [Google Scholar] [CrossRef]
  514. Solmaz, I.; Gurkanlar, D.; Gökçil, Z.; Goksoy, C.; Özkan, M.; Erdogan, E. Antiepileptic activity of melatonin in guinea pigs with pentylenetetrazol-induced seizures. Neurol. Res. 2009, 31, 989–995. [Google Scholar] [CrossRef] [PubMed]
  515. Janjoppi, L.; De Lacerda, A.F.S.; Scorza, F.A.; Amado, D.; Cavalheiro, E.; Arida, R.M. Influence of pinealectomy on the amygdala kindling development in rats. Neurosci. Lett. 2006, 392, 150–153. [Google Scholar] [CrossRef] [PubMed]
  516. De Lima, E.; Soares, J.M.; Garrido, Y.D.C.S.; Valente, S.; Priel, M.R.; Baracat, E.C.; Cavalheiro, E.; Mazzacoratti, M.D.G.N.; Amado, D. Effects of pinealectomy and the treatment with melatonin on the temporal lobe epilepsy in rats. Brain Res. 2005, 1043, 24–31. [Google Scholar] [CrossRef]
  517. Lee, S.-H.; Chun, W.; Kong, P.-J.; Han, J.A.; Cho, B.P.; Kwon, O.-Y.; Lee, H.J.; Kim, S.-S. Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus. J. Pineal Res. 2006, 40, 79–85. [Google Scholar] [CrossRef] [PubMed]
  518. Chung, S.-Y.; Han, S.-H. Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition. J. Pineal Res. 2003, 34, 95–102. [Google Scholar] [CrossRef]
  519. Tchekalarova, J.; Petkova, Z.; Pechlivanova, D.; Moyanova, S.G.; Kortenska, L.; Mitreva, R.; Lozanov, V.; Atanasova, D.; Lazarov, N.; Stoynev, A.; et al. Prophylactic treatment with melatonin after status epilepticus: Effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy. Epilepsy Behav. 2013, 27, 174–187. [Google Scholar] [CrossRef] [PubMed]
  520. Lima, E.; Cabral, F.R.; Cavalheiro, E.; Mazzacoratti, M.D.G.N.; Amado, D. Melatonin administration after pilocarpine-induced status epilepticus: A new way to prevent or attenuate postlesion epilepsy? Epilepsy Behav. 2011, 20, 607–612. [Google Scholar] [CrossRef]
  521. Kazemi, M.; Shokri, S.; Ganjkhani, M.; Ali, R.; Iraj, J.A. Modulation of axonal sprouting along rostro-caudal axis of dorsal hippocampus and no neuronal survival in parahippocampal cortices by long-term post-lesion melatonin administration in lithium-pilocarpine model of temporal lobe epilepsy. Anat. Cell Biol. 2016, 49, 21–33. [Google Scholar] [CrossRef] [Green Version]
  522. Rocha, A.K.A.D.A.; De Lima, E.; Amaral, F.G.; Peres, R.; Cipolla-Neto, J.; Amado, D. Altered MT1 and MT2 melatonin receptors expression in the hippocampus of pilocarpine-induced epileptic rats. Epilepsy Behav. 2017, 71, 23–34. [Google Scholar] [CrossRef]
  523. Fenoglio-Simeone, K.; Mazarati, A.; Sefidvash-Hockley, S.; Shin, D.; Wilke, J.; Milligan, H.; Sankar, R.; Rho, J.M.; Maganti, R. Anticonvulsant effects of the selective melatonin receptor agonist ramelteon. Epilepsy Behav. 2009, 16, 52–57. [Google Scholar] [CrossRef] [PubMed]
  524. Bialer, M.; Johannessen, S.I.; Levy, R.H.; Perucca, E.; Tomson, T.; White, H.S. Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII). Epilepsy Res. 2015, 111, 85–141. [Google Scholar] [CrossRef]
  525. Tchekalarova, J.; Atanasova, D.; Nenchovska, Z.; Atanasova, M.; Kortenska, L.; Gesheva, R.; Lazarov, N. Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy. Neurobiol. Dis. 2017, 104, 1–14. [Google Scholar] [CrossRef] [PubMed]
  526. Ardura, J.; Andres, J.; Garmendia, J.R.; Ardura, F. Melatonin in Epilepsy and Febrile Seizures. J. Child Neurol. 2010, 25, 888–891. [Google Scholar] [CrossRef] [PubMed]
  527. Dabak, O.; Altun, D.; Arslan, M.; Yaman, H.; Vurucu, S.; Yesilkaya, E.; Unay, B. Evaluation of Plasma Melatonin Levels in Children With Afebrile and Febrile Seizures. Pediatr. Neurol. 2016, 57, 51–55. [Google Scholar] [CrossRef] [PubMed]
  528. Bazil, C.W.; Short, D.; Crispin, D.; Zheng, W. Patients with intractable epilepsy have low melatonin, which increases following seizures. Neurology 2000, 55, 1746–1748. [Google Scholar] [CrossRef] [Green Version]
  529. Elkhayat, H.A.; Hassanein, S.M.; Tomoum, H.Y.; Abd-Elhamid, I.A.; Asaad, T.; Elwakkad, A.S. Melatonin and Sleep-Related Problems in Children With Intractable Epilepsy. Pediatr. Neurol. 2010, 42, 249–254. [Google Scholar] [CrossRef]
  530. Peled, N.; Shorer, Z.; Peled, E.; Pillar, G. Melatonin Effect on Seizures in Children with Severe Neurologic Deficit Disorders. Epilepsia 2002, 42, 1208–1210. [Google Scholar] [CrossRef]
  531. Molina-Carballo, A.; Hoyos, A.M.; Reiter, R.J.; Sánchez-Forte, M.; Moreno-Madrid, F.; Rufo-Campos, M.; Molina-Font, J.A.; Acuña-Castroviejo, D. Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: Two years’ experience. J. Pineal Res. 1997, 23, 97–105. [Google Scholar] [CrossRef]
  532. Gupta, M.; Gupta, Y.K.; Agarwal, S.; Aneja, S.; Kalaivani, M.; Kohli, K. Effects of Add-on Melatonin Administration on Antioxidant Enzymes in Children with Epilepsy Taking Carbamazepine Monotherapy: A Randomized, Double-blind, Placebo-controlled Trial. Epilepsia 2004, 45, 1636–1639. [Google Scholar] [CrossRef] [PubMed]
  533. Gupta, M.; Gupta, Y.K.; Agarwal, S.; Aneja, S.; Kohli, K. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: Effect on glutathione peroxidase and glutathione reductase enzymes. Br. J. Clin. Pharmacol. 2004, 58, 542–547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  534. Sheldon, S.H. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998, 351, 1254. [Google Scholar] [CrossRef]
  535. Sandyk, R.; Tsagas, N.; Anninos, P. Melatonin as a Proconvulsive Hormone in Humans. Int. J. Neurosci. 1992, 63, 125–135. [Google Scholar] [CrossRef] [PubMed]
  536. Jan, J.E.; Hamilton, D.; Seward, N.; Fast, D.K.; Freeman, R.D.; Laudon, M. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J. Pineal Res. 2000, 29, 34–39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  537. Ross, C.; Davies, P.; Whitehouse, W. Melatonin treatment for sleep disorders in children with neurodevelopmental disorders: An observational study. Dev. Med. Child Neurol. 2002, 44, 339–344. [Google Scholar] [CrossRef]
  538. Jones, C.; Huyton, M.; Hindley, D. Melatonin and epilepsy. Arch. Dis. Child. 2005, 90, 1203. [Google Scholar] [CrossRef] [Green Version]
  539. Yu, Y.; Nguyen, D.T.; Jiang, J. G protein-coupled receptors in acquired epilepsy: Druggability and translatability. Prog. Neurobiol. 2019, 183, 101682. [Google Scholar] [CrossRef]
  540. Oliveira, M.; Furian, A.F.; Rambo, L.M.; Ribeiro, L.R.; Royes, L.; Ferreira, J.A.; Calixto, J.B.; Mello, C.F. Modulation of pentylenetetrazol-induced seizures by prostaglandin E2 receptors. Neuroscience 2008, 152, 1110–1118. [Google Scholar] [CrossRef]
  541. Pekcec, A.; Unkrüer, B.; Schlichtiger, J.; Soerensen, J.; Hartz, A.M.S.; Bauer, B.; Van Vliet, E.A.; Gorter, J.A.; Potschka, H. Targeting Prostaglandin E2 EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation. J. Pharmacol. Exp. Ther. 2009, 330, 939–947. [Google Scholar] [CrossRef] [Green Version]
  542. Fischborn, S.V.; Soerensen, J.; Potschka, H. Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice. Epilepsy Res. 2010, 91, 57–65. [Google Scholar] [CrossRef]
  543. Reschke, C.R.; Poersch, A.B.; Masson, C.J.; Jesse, A.C.; Marafiga, J.R.; Lenz, Q.F.; Oliveira, M.S.; Henshall, D.C.; Mello, C.F. Systemic delivery of selective EP1 and EP3 receptor antagonists attenuates pentylenetetrazole-induced seizures in mice. Int. J. Physiol. Pathophysiol. Pharmacol. 2018, 10, 47–59. [Google Scholar]
  544. Jiang, J.; Ganesh, T.; Du, Y.; Quan, Y.; Serrano, G.; Qui, M.; Speigel, I.; Rojas, A.; Lelutiu, N.; Dingledine, R. Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2. Proc. Natl. Acad. Sci. USA 2012, 109, 3149–3154. [Google Scholar] [CrossRef] [Green Version]
  545. Jiang, J.; Quan, Y.; Ganesh, T.; Pouliot, W.A.; Dudek, F.E.; Dingledine, R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc. Natl. Acad. Sci. USA 2013, 110, 3591–3596. [Google Scholar] [CrossRef] [Green Version]
  546. Jiang, J.; Yang, M.-S.; Quan, Y.; Gueorguieva, P.; Ganesh, T.; Dingledine, R. Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol. Dis. 2015, 76, 126–136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  547. Jiang, J.; Yu, Y.; Kinjo, E.R.; Du, Y.; Nguyen, H.P.; Dingledine, R. Suppressing pro-inflammatory prostaglandin signaling attenuates excitotoxicity-associated neuronal inflammation and injury. Neuropharmacology 2019, 149, 149–160. [Google Scholar] [CrossRef] [PubMed]
  548. Rojas, A.; Gueorguieva, P.; Lelutiu, N.; Quan, Y.; Shaw, R.; Dingledine, R. The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. Neurobiol. Dis. 2014, 70, 74–89. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  549. Rojas, A.; Ganesh, T.; Lelutiu, N.; Gueorguieva, P.; Dingledine, R. Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus. Neuropharmacology 2015, 93, 15–27. [Google Scholar] [CrossRef] [Green Version]
  550. Rojas, A.; Ganesh, T.; Manji, Z.; O’Neill, T.; Dingledine, R. Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats. Neuropharmacology 2016, 110, 419–430. [Google Scholar] [CrossRef] [Green Version]
  551. Kim, H.-J.; Chung, J.-I.; Lee, S.H.; Jung, Y.-S.; Moon, C.-H.; Baik, E.J. Involvement of endogenous prostaglandin F2α on kainic acid-induced seizure activity through FP receptor: The mechanism of proconvulsant effects of COX-2 inhibitors. Brain Res. 2008, 1193, 153–161. [Google Scholar] [CrossRef]
  552. Chung, J.-I.; Kim, A.Y.; Lee, S.H.; Baik, E.J. Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2α. Exp. Neurol. 2013, 249, 95–103. [Google Scholar] [CrossRef] [PubMed]
  553. Nagib, M.M.; Yu, Y.; Jiang, J. Targeting prostaglandin receptor EP2 for adjunctive treatment of status epilepticus. Pharmacol. Ther. 2020, 209, 107504. [Google Scholar] [CrossRef] [PubMed]
  554. Mechoulam, R.; Parker, L.A. The Endocannabinoid System and the Brain. Annu. Rev. Psychol. 2013, 64, 21–47. [Google Scholar] [CrossRef] [Green Version]
  555. Atwood, B.K.; Mackie, K. CB2: A cannabinoid receptor with an identity crisis. Br. J. Pharmacol. 2010, 160, 467–479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  556. Busquets-Garcia, A.; Bains, J.; Marsicano, G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacology 2018, 43, 4–20. [Google Scholar] [CrossRef]
  557. DeMuth, D.G.; Molleman, A. Cannabinoid signalling. Life Sci. 2006, 78, 549–563. [Google Scholar] [CrossRef]
  558. Zavala-Tecuapetla, C.; Rocha, L. Chapter 5: Do cannabinoids represent a good therapeutic strategy for epilepsy? In Antiepileptic Drug Discovery: Novel Approaches; Talevi, A., Rocha, L., Eds.; Humana Press: New York, NY, USA, 2016; pp. 83–96. ISBN 978-1-4939-6353-9. [Google Scholar]
  559. Cheung, K.A.K.; Peiris, H.; Wallace, G.; Holland, O.J.; Mitchell, M.D. The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids. Int. J. Mol. Sci. 2019, 20, 6079. [Google Scholar] [CrossRef] [Green Version]
  560. Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.; Eder, M.; Cannich, A.; Azad, S.C.; Cascio, M.G.; Gutiérrez, S.O.; Van Der Stelt, M.; et al. CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity. Science 2003, 302, 84–88. [Google Scholar] [CrossRef] [Green Version]
  561. Blair, R.E.; Deshpande, L.S.; Sombati, S.; Falenski, K.W.; Martin, B.R.; DeLorenzo, R.J.; Kinney, G.G.; Burno, M.; Campbell, U.C.; Hernández, L.M.; et al. Activation of the Cannabinoid Type-1 Receptor Mediates the Anticonvulsant Properties of Cannabinoids in the Hippocampal Neuronal Culture Models of Acquired Epilepsy and Status Epilepticus. J. Pharmacol. Exp. Ther. 2006, 317, 1072–1078. [Google Scholar] [CrossRef] [Green Version]
  562. Kow, R.L.; Jiang, K.; Naydenov, A.V.; Le, J.H.; Stella, N.; Nathanson, N.M. Modulation of Pilocarpine-Induced Seizures by Cannabinoid Receptor 1. PLoS ONE 2014, 9, e95922. [Google Scholar] [CrossRef]
  563. Sugaya, Y.; Yamazaki, M.; Uchigashima, M.; Kobayashi, K.; Watanabe, M.; Sakimura, K.; Kano, M. Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures. Cell Rep. 2016, 16, 1405–1415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  564. Rowley, S.; Sun, X.; Lima, I.V.; Tavenier, A.; De Oliveira, A.C.P.; Dey, S.K.; Danzer, S.C. Cannabinoid receptor 1/2 double-knockout mice develop epilepsy. Epilepsia 2017, 58, e162–e166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  565. Yu, Y.; Li, L.; Nguyen, D.T.; Mustafa, S.M.; Moore, B.M.; Jiang, J. Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics. Mol. Neurobiol. 2020, 57, 2830–2845. [Google Scholar] [CrossRef] [PubMed]
  566. Ludányi, A.; Erőss, L.; Czirják, S.; Vajda, J.; Halász, P.; Watanabe, M.; Palkovits, M.; Maglóczky, Z.; Freund, T.F.; Katona, I. Downregulation of the CB1 Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus. J. Neurosci. 2008, 28, 2976–2990. [Google Scholar] [CrossRef] [Green Version]
  567. Rocha, L.; Cinar, R.; Guevara-Guzmán, R.; Alonso-Vanegas, M.; San-Juan, D.; Martínez-Juárez, I.; Castañeda-Cabral, J.L.; Carmona-Cruz, F. Endocannabinoid System and Cannabinoid 1 Receptors in Patients With Pharmacoresistant Temporal Lobe Epilepsy and Comorbid Mood Disorders. Front. Behav. Neurosci. 2020, 14. [Google Scholar] [CrossRef] [PubMed]
  568. Klein, R.; Nanduri, V.; Jing, S.; Lamballe, F.; Tapley, P.; Bryant, S.; Cordon-Cardo, C.; Jones, K.R.; Reichardt, L.F.; Barbacid, M. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 1991, 66, 395–403. [Google Scholar] [CrossRef]
  569. Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009, 10, 850–860. [Google Scholar] [CrossRef]
  570. McNamara, J.O.; Scharfman, H.E. Temporal Lobe Epilepsy and the BDNF Receptor, TrkB. In Jasper’s Basic Mechanisms of the Epilepsies [Internet], 4th ed.; Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., Delgado-Escueta, A.V., Eds.; National Center for Biotechnology Information: Bethesda, MD, USA, 2012. [Google Scholar]
  571. Lin, T.W.; Harward, S.C.; Huang, Y.Z.; McNamara, J.O. Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy. Neuropharmacology 2020, 167, 107734. [Google Scholar] [CrossRef]
  572. Isackson, P.J.; Huntsman, M.M.; Murray, K.D.; Gall, C.M. BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: Temporal patterns of induction distinct from NGF. Neuron 1991, 6, 937–948. [Google Scholar] [CrossRef]
  573. Takahashi, M.; Hayashi, S.; Kakita, A.; Wakabayashi, K.; Fukuda, M.; Kameyama, S.; Tanaka, R.; Takahashi, H.; Nawa, H. Patients with temporal lobe epilepsy show an increase in brain-derived neurotrophic factor protein and its correlation with neuropeptide Y. Brain Res. 1999, 818, 579–582. [Google Scholar] [CrossRef]
  574. Xu, B.; Michalski, B.; Racine, R.; Fahnestock, M. The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. Neuroscience 2004, 126, 521–531. [Google Scholar] [CrossRef] [PubMed]
  575. Thomas, A.X.; Del Angel, Y.C.; González, M.I.; Carrel, A.J.; Carlsen, J.; Lam, P.M.; Hempstead, B.L.; Russek, S.J.; Brooks-Kayal, A. Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery. eNeuro 2016, 3, 0020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  576. Binder, D.K.; Routbort, M.J.; Ryan, T.E.; Yancopoulos, G.D.; McNamara, J.O. Selective Inhibition of Kindling Development by Intraventricular Administration of TrkB Receptor Body. J. Neurosci. 1999, 19, 1424–1436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  577. He, X.-P.; Minichiello, L.; Klein, R.; McNamara, J.O. Immunohistochemical Evidence of Seizure-Induced Activation of trkB Receptors in the Mossy Fiber Pathway of Adult Mouse Hippocampus. J. Neurosci. 2002, 22, 7502–7508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  578. He, X.-P.; Kotloski, R.; Nef, S.; Luikart, B.W.; Parada, L.F.; McNamara, J.O. Conditional Deletion of TrkB but Not BDNF Prevents Epileptogenesis in the Kindling Model. Neuron 2004, 43, 31–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  579. He, X.P.; Pan, E.; Sciarretta, C.; Minichiello, L.; McNamara, J.O. Disruption of TrkB-Mediated Phospholipase C Signaling Inhibits Limbic Epileptogenesis. J. Neurosci. 2010, 30, 6188–6196. [Google Scholar] [CrossRef] [Green Version]
  580. Liu, G.; Gu, B.; He, X.-P.; Joshi, R.B.; Wackerle, H.D.; Rodriguiz, R.M.; Wetsel, W.C.; McNamara, J.O. Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy. Neuron 2013, 79, 31–38. [Google Scholar] [CrossRef] [Green Version]
  581. Gu, B.; Huang, Y.Z.; He, X.-P.; Joshi, R.B.; Jang, W.; McNamara, J.O. A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus. Neuron 2015, 88, 484–491. [Google Scholar] [CrossRef] [Green Version]
  582. Yu, Y.; Jiang, J. COX-2/PGE 2 axis regulates hippocampal BDNF/TrkB signaling via EP2 receptor after prolonged seizures. Epilepsia Open 2020, 5, 418–431. [Google Scholar] [CrossRef]
  583. Falcicchia, C.; Paolone, G.; Emerich, D.F.; Lovisari, F.; Bell, W.J.; Fradet, T.; Wahlberg, L.U.; Simonato, M. Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy. Mol. Ther. Methods Clin. Dev. 2018, 9, 211–224. [Google Scholar] [CrossRef] [Green Version]
  584. Shestopalov, V.I.; Slepak, V.Z. Molecular pathways of pannexin1-mediated neurotoxicity. Front. Physiol. 2014, 5, 23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  585. Scemes, E.; Velíšková, J. Exciting and not so exciting roles of pannexins. Neurosci. Lett. 2019, 695, 25–31. [Google Scholar] [CrossRef] [PubMed]
  586. Aquilino, M.S.; Whyte-Fagundes, P.; Zoidl, G.; Carlen, P.L. Pannexin-1 channels in epilepsy. Neurosci. Lett. 2019, 695, 71–75. [Google Scholar] [CrossRef] [PubMed]
  587. Bruzzone, R.; Hormuzdi, S.G.; Barbe, M.T.; Herb, A.; Monyer, H. Pannexins, a family of gap junction proteins expressed in brain. Proc. Natl. Acad. Sci. USA 2003, 100, 13644–13649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  588. Vogt, A.; Hormuzdi, S.G.; Monyer, H. Pannexin1 and Pannexin2 expression in the developing and mature rat brain. Mol. Brain Res. 2005, 141, 113–120. [Google Scholar] [CrossRef]
  589. Zoidl, G.; Petrasch-Parwez, E.; Ray, A.; Meier, C.; Bunse, S.; Habbes, H.-W.; Dahl, G.; Dermietzel, R. Localization of the pannexin1 protein at postsynaptic sites in the cerebral cortex and hippocampus. Neuroscience 2007, 146, 9–16. [Google Scholar] [CrossRef]
  590. Cone, A.C.; Ambrosi, C.; Scemes, E.; Martone, M.E.; Sosinsky, G.E. A Comparative Antibody Analysis of Pannexin1 Expression in Four Rat Brain Regions Reveals Varying Subcellular Localizations. Front. Pharmacol. 2013, 4, 6. [Google Scholar] [CrossRef] [Green Version]
  591. Heinrich, A.; Andó, R.; Turi, G.; Rozsa, B.; Sperlágh, B. K+depolarization evokes ATP, adenosine and glutamate release from glia in rat hippocampus: A microelectrode biosensor study. Br. J. Pharmacol. 2012, 167, 1003–1020. [Google Scholar] [CrossRef] [Green Version]
  592. Thompson, R.J.; Jackson, M.F.; Olah, M.E.; Rungta, R.L.; Hines, D.J.; Beazely, M.A.; Macdonald, J.F.; MacVicar, B.A. Activation of Pannexin-1 Hemichannels Augments Aberrant Bursting in the Hippocampus. Science 2008, 322, 1555–1559. [Google Scholar] [CrossRef] [Green Version]
  593. Santiago, M.F.; Velísková, J.; Patel, N.K.; Lutz, S.E.; Caille, D.; Charollais, A.; Meda, P.; Scemes, E. Targeting Pannexin1 Improves Seizure Outcome. PLoS ONE 2011, 6, e25178. [Google Scholar] [CrossRef] [Green Version]
  594. Kim, J.-E.; Kang, T.-C. The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice. J. Clin. Investig. 2011, 121, 2037–2047. [Google Scholar] [CrossRef] [Green Version]
  595. Aquilino, M.S.; Whyte-Fagundes, P.; Lukewich, M.K.; Zhang, L.; Bardakjian, B.L.; Zoidl, G.; Carlen, P.L. Pannexin-1 Deficiency Decreases Epileptic Activity in Mice. Int. J. Mol. Sci. 2020, 21, 7510. [Google Scholar] [CrossRef] [PubMed]
  596. Mylvaganam, S.; Zhang, L.; Wu, C.; Zhang, Z.J.; Samoilova, M.; Eubanks, J.; Carlen, P.L.; Poulter, M.O. Hippocampal seizures alter the expression of the pannexin and connexin transcriptome. J. Neurochem. 2010, 112, 92–102. [Google Scholar] [CrossRef]
  597. Jiang, T.; Long, H.; Ma, Y.; Long, L.-L.; Li, Y.; Li, F.; Zhou, P.; Yuan, C.; Xiao, B. Altered expression of pannexin proteins in patients with temporal lobe epilepsy. Mol. Med. Rep. 2013, 8, 1801–1806. [Google Scholar] [CrossRef] [Green Version]
  598. Cepeda, C.; Chang, J.W.; Owens, G.C.; Huynh, M.N.; Chen, J.Y.; Tran, C.; Vinters, H.V.; Levine, M.S.; Mathern, G.W. In Rasmussen Encephalitis, Hemichannels Associated with Microglial Activation are linked to Cortical Pyramidal Neuron Coupling: A Possible Mechanism for Cellular Hyperexcitability. CNS Neurosci. Ther. 2014, 21, 152–163. [Google Scholar] [CrossRef]
  599. Li, S.; Zang, Z.; He, J.; Chen, X.; Yu, S.; Pei, Y.; Hou, Z.; An, N.; Yang, H.; Zhang, C.; et al. Expression of pannexin 1 and 2 in cortical lesions from intractable epilepsy patients with focal cortical dysplasia. Oncotarget 2016, 8, 6883–6895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  600. Dossi, E.; Blauwblomme, T.; Moulard, J.; Chever, O.; Vasile, F.; Guinard, E.; Le Bert, M.; Couillin, I.; Pallud, J.; Capelle, L.; et al. Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy. Sci. Transl. Med. 2018, 10, eaar3796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. Overview of Wnt/β-catenin pathway. In the absence of Wnt stimulation (Wnt OFF), cytoplasmic levels of β-catenin are low since it is phosphorylated by the destruction complex, resulting in recognition and proteasomal degradation. Once the Wnt-Fz-LRP5/6 interaction (Wnt ON) has started, the destruction complex is disassembled and therefore the proteasomal degradation of β-catenin is prevented. In this way, β-catenin accumulates within the cytoplasm and translocates to the nucleus, where it binds to the transcription factors (T-cell factor and lymphoid enhancer factor (TCF/LEF)) to finally activate the transcription of Wnt target genes. LRP5/6, lipoprotein receptor-related protein 5 or 6; Fzd, receptor frizzled; Dvl, dishevelled; APC, adenomatous polyposis coli; CK1α, casein kinase 1α; GSK3β, glycogen synthase kinase 3β.
Figure 1. Overview of Wnt/β-catenin pathway. In the absence of Wnt stimulation (Wnt OFF), cytoplasmic levels of β-catenin are low since it is phosphorylated by the destruction complex, resulting in recognition and proteasomal degradation. Once the Wnt-Fz-LRP5/6 interaction (Wnt ON) has started, the destruction complex is disassembled and therefore the proteasomal degradation of β-catenin is prevented. In this way, β-catenin accumulates within the cytoplasm and translocates to the nucleus, where it binds to the transcription factors (T-cell factor and lymphoid enhancer factor (TCF/LEF)) to finally activate the transcription of Wnt target genes. LRP5/6, lipoprotein receptor-related protein 5 or 6; Fzd, receptor frizzled; Dvl, dishevelled; APC, adenomatous polyposis coli; CK1α, casein kinase 1α; GSK3β, glycogen synthase kinase 3β.
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Figure 2. Simplified schematic representation of the hyperactivated mammalian target of rapamycin (mTOR) signaling due to seizures. Once the mTOR pathway is activated, it acts on subsequent effectors to suppress autophagy, as well as promote protein synthesis and cell survival related to the epileptogenesis process. Arrows and bars represent activation and inhibition, respectively. PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; TSC1/TSC2, tumor suppressor complex 1/2; Rheb, ras homolog enriched in brain; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; S6K, ribosomal S6 kinase.
Figure 2. Simplified schematic representation of the hyperactivated mammalian target of rapamycin (mTOR) signaling due to seizures. Once the mTOR pathway is activated, it acts on subsequent effectors to suppress autophagy, as well as promote protein synthesis and cell survival related to the epileptogenesis process. Arrows and bars represent activation and inhibition, respectively. PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; TSC1/TSC2, tumor suppressor complex 1/2; Rheb, ras homolog enriched in brain; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; S6K, ribosomal S6 kinase.
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Figure 3. Overview of the complement system. Complement activation can be initiated by three distinct pathways: the classical, lectin and alternative pathways. Although each one is activated in response to different molecules, all of them manage to activate complement factors (C3 and C5) and promote the release of anaphylatoxins (C3a and C5a) associated with inflammatory processes. Complement activation ends with the membrane attack complex (MAC; C5b–C9) formation which can then cause targeted cell lysis.
Figure 3. Overview of the complement system. Complement activation can be initiated by three distinct pathways: the classical, lectin and alternative pathways. Although each one is activated in response to different molecules, all of them manage to activate complement factors (C3 and C5) and promote the release of anaphylatoxins (C3a and C5a) associated with inflammatory processes. Complement activation ends with the membrane attack complex (MAC; C5b–C9) formation which can then cause targeted cell lysis.
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Zavala-Tecuapetla, C.; Cuellar-Herrera, M.; Luna-Munguia, H. Insights into Potential Targets for Therapeutic Intervention in Epilepsy. Int. J. Mol. Sci. 2020, 21, 8573. https://doi.org/10.3390/ijms21228573

AMA Style

Zavala-Tecuapetla C, Cuellar-Herrera M, Luna-Munguia H. Insights into Potential Targets for Therapeutic Intervention in Epilepsy. International Journal of Molecular Sciences. 2020; 21(22):8573. https://doi.org/10.3390/ijms21228573

Chicago/Turabian Style

Zavala-Tecuapetla, Cecilia, Manola Cuellar-Herrera, and Hiram Luna-Munguia. 2020. "Insights into Potential Targets for Therapeutic Intervention in Epilepsy" International Journal of Molecular Sciences 21, no. 22: 8573. https://doi.org/10.3390/ijms21228573

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