IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings
Graphical abstract
Introduction
It is recognized that convulsions begin to occur when initially sub-convulsive doses are injected repeatedly (Davis, 1996). Earlier studies have indicated that repetitive exposure of sub-convulsive doses of cocaine is also associated with an increased risk of convulsive behaviors in rodents and monkeys (Miller et al., 2000; Post and Kopanda, 1975, 1976; Post and Rose, 1976; Stripling and Ellinwood, 1977; Tatum and Seevers, 1929). Repeated administration of sub-convulsive doses of cocaine can increase sensitivity to its convulsant effect, a phenomenon called kindling that is analogous to the kindling of epileptic seizures engendered by repetitive sub-threshold electrical stimulation of the limbic system (Goddard et al., 1969). Cocaine-kindling behaviors have been recognized as an advantageous model for studying the psychopathology and toxicity associated with cocaine abuse (Miller et al., 2000). Indeed, prolonged cocaine abuse is not only associated with increases in seizure probability (Alldredge et al., 1989; Dhuna et al., 1991), but also with violent behaviors (Richards et al., 1998; Ruttenber et al., 1997) and panic disorders (Louie et al., 1989). Overlapping pharmacological mechanisms have been proposed to elucidate those neurological and behavioral disorders (Post, 2002).
Neuroprotective and adaptive responses to cocaine-induced neurotoxicity and neurodegenerative processes include cerebral up-regulation of neurotrophic cytokines, including pleiotrophin (PTN) and midkine (Vicente-Rodriguez et al., 2013, 2015). Some of the signaling pathways triggered by PTN are important in the neuroprotective roles of those cytokines against cocaine-induced neurotoxicity (Herradon and Perez-Garcia, 2014). For example, PTN has been shown to prevent cocaine-induced cytotoxicity in NG108-15 and PC12 cell cultures (Gramage et al., 2008; Herradon et al., 2009). In addition, evidence points to a modulatory role for PTN in inflammation. PTN induced the expression of various cytokines, including tumor necrosis factor (TNF-α) and interleukin (IL)-6, in peripheral organs (Achour et al., 2008). TNF-α and IL-6 levels increased significantly in response to lipopolysaccharide in PTN-transgenic mice (Fernandez-Calle et al., 2017).
Increasing evidence suggests that cytokines participate not only in functions related to the immune system, but also in complex functions of the central nervous system, such as seizures (Dey et al., 2016; Li et al., 2011). In particular, IL-6 is reported to modulate seizure activity (Alapirtti et al., 2018; Ambrogini et al., 2018; Li et al., 2011). We previously demonstrated that IL-6 protects against trimethyltin (TMT)-induced excitotoxicity via an Nrf-2-dependent glutathione defense mechanism and phosphoinositide 3-kinase (PI3K)/Akt-dependent signaling (Tran et al., 2012). We also observed that recombinant IL-6 protein (rIL-6) significantly inhibited memory impairments induced by TMT in IL-6 knockout (KO) mice (Kim et al., 2013). The administration of pituitary adenylate cyclase-activating polypeptide (PACAP) to wild-type (WT) mice significantly increased IL-6 level in the cerebrospinal fluid and IL-6 mRNA expression in the brain, indicating that IL-6 is an important factor mediating the neuroprotective effect of PACAP in response to brain ischemia (Ohtaki et al., 2006).
The neuroprotective activities of endogenous PACAP have been evaluated using PACAP KO mice, which exhibit worse neurologic symptoms after middle cerebral artery occlusion than WT mice (Nakamachi et al., 2010; Reglodi et al., 2012). In addition, PACAP protects nerve cells through the inhibition of cytochrome C release from the mitochondria (Ohtaki et al., 2006), and promoted the secretion of IL-6 from astrocytes and Müller cells (Nakatani et al., 2006; Tatsuno et al., 1996). IL-6-induced up-regulation of growth factors known to act in the induction of PACAP, which could have an important effect on IL-6-induced PC12 cell differentiation (Ravni et al., 2006). Microarray analyses of PACAP-regulated gene transcripts revealed that many gene families that are activated by PACAP in primary sympathetic neurons were also induced by IL-6 in PC12 cells (Braas et al., 2007). Therefore, it is plausible that the effects of IL-6 are mediated by the intermediate action of PACAP.
The neuroprotective properties of PACAP have been established in ischemic neuronal injuries (Ohtaki et al., 2006; Reglodi et al., 2018; Shioda and Nakamachi, 2015). Lower levels of phosphorylated STAT3 and phosphorylated ERK were observed in PACAP ± mice, whereas a reduction in phosphorylated STAT3 was recorded in IL-6 KO mice, suggesting that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6 and STAT3 (Ohtaki et al., 2006). Because IL-6 also modulates convulsive behaviors (Tran et al., 2012; Tu et al., 2017), we designed the present study to explore the roles of IL-6 and PACAP in the expression and development of cocaine-kindling behaviors. We propose that PACAP is an important modulator of IL-6-mediated anticonvulsant protection against cocaine insult.
Section snippets
Animals
All mice were treated in strict accordance with the NIH Guide for the Humane Care and Use of Laboratory Animals. Eight-week-old male C57BL/6 (WT) mice, male IL-6 KO mice, and male TNF-α KO mice weighing 25 ± 3 g were used for this study. WT animals were purchased from Orient Bio Inc. (Charles River Technology, Seoul, Korea). We used IL-6 KO and TNF-α KO mice of the C57BL/6 background strain, as previously reported (Clark et al., 2000; Hoshi et al., 2009; Kim et al., 2013; Sudo et al., 2008;
Cocaine-induced changes in the expression of cytokines (IL-6, IFN-γ, and TNF-α), phospho-JAK2/STAT3, and PACAP/PAC1R in the hippocampus of mice
We conducted a time-course study to assess changes in mRNA and protein expression of IL-6, IFN-γ, and TNF-α after the final treatment of cocaine. IL-6 mRNA and protein expression increased significantly after cocaine treatment over the entire time-course (Fig. 1A and B). Notably, an initial increase in IL-6 mRNA and protein levels was observed 1 h after the final cocaine treatment (P < 0.05 vs. saline); this increase lasted for at least 14 d and peaked after 6 h and 12 h (mRNA: 1 h, 1 d, 3 d,
Discussion
We observed that cocaine treatment initially (within 1 h) induced IL-6 gene expression that lasted for at least 7 d, and that cocaine-induced alterations in IFN-γ or TNFα gene expression were less pronounced. Our results indicate that cocaine-induced kindling behaviors in IL-6 KO mice is more pronounced than in TNF-α KO mice. rIL-6 significantly restored the activation of JAK2/STAT3 signaling and the PACAP/PAC1 receptor in the IL-6 deficient condition, thereby increasing expression of Bcl-2 and
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgements
This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and (#NRF-2017R1A2B1003346 and #NRF-2016R1A1A1A05005201), Republic of Korea, and by a grant from Hungarian Brain Research Program 20017-1.2.1-NKP -2017-00002, MTA-TKI 14016, EFOP-3.6.2-16-2017-00008/(The role of neuro-inflammation in neurodegeneration: from molecules to
References (80)
- et al.
Pleiotrophin induces expression of inflammatory cytokines in peripheral blood mononuclear cells
Biochimie
(2008) - et al.
The production of IL-6 in acute epileptic seizure: a video-EEG study
J. Neuroimmunol.
(2018) - et al.
Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: a video-EEG study
J. Neurol. Sci.
(2009) - et al.
Etiology and site of temporal lobe epilepsy influence postictal cytokine release
Epilepsy Res.
(2009) - et al.
Microarray analyses of pituitary adenylate cyclase activating polypeptide (PACAP)-regulated gene targets in sympathetic neurons
Peptides
(2007) Psychopharmacologic violence associated with cocaine abuse: kindling of limbic dyscontrol symdrome?
Prog. Neuro Psychopharmacol. Biol. Psychiatr.
(1996)- et al.
Susceptibility to audiogenic seizure and neurotransmitter amino acid levels in different brain areas of IL-6-deficient mice
Pharmacol. Biochem. Behav.
(2004) - et al.
Seizure susceptibility to various convulsant stimuli of knockout interleukin-6 mice
Pharmacol. Biochem. Behav.
(2004) - et al.
Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside
Trends Pharmacol. Sci.
(2016) - et al.
Interleukin-6 attenuates hyperthermia-induced seizures in developing rats
Brain Dev.
(2007)
Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity
Brain Behav. Immun.
A permanent change in brain function resulting from daily electrical stimulation
Exp. Neurol.
Acute cocaine-induced seizures: differential sensitivity of six inbred mouse strains
Neuropsychopharmacology
Pleiotrophin prevents cocaine-induced toxicity in vitro
Eur. J. Pharmacol.
Marked increases in hippocampal neuron indoleamine 2, 3-dioxygenase via IFN-gamma-independent pathway following transient global ischemia in mouse
Neurosci. Res.
IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2/STAT3, M1 mAChR and ERK signaling network
Cell. Signal.
Excitatory action of pituitary adenylate cyclase activating polypeptide on rat sympathetic preganglionic neurons in vivo and in vitro
Brain Res.
Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration
J. Neuroimmunol.
Cytokines and epilepsy
Seizure
Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells
Am. J. Pathol.
Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway
J. Biol. Chem.
Pituitary adenylate cyclase-activating peptide (PACAP) stimulates production of interleukin-6 in rat Muller cells
Peptides
Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures
Epilepsy Res.
Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures
Neuroscience
Prevention of neuron and oligodendrocyte degeneration by interleukin-6 (IL-6) and IL-6 receptor/IL-6 fusion protein in organotypic hippocampal slices
Mol. Cell. Neurosci.
Do the epilepsies, pain syndromes, and affective disorders share common kindling-like mechanisms?
Epilepsy Res.
Cocaine, kindling and reverse tolerance
Lancet
Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol
J. Emerg. Med.
PKCdelta knockout mice are protected from para-methoxymethamphetamine-induced mitochondrial stress and associated neurotoxicity in the striatum of mice
Neurochem. Int.
PACAP as a neuroprotective factor in ischemic neuronal injuries
Peptides
Potentiation of the behavioral and convulsant effects of cocaine by chronic administration in the rat
Pharmacol. Biochem. Behav.
TNF-alpha and IL-6 signals from the bone marrow derived cells are necessary for normal murine liver regeneration
Biochim. Biophys. Acta
Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo
Free Radic. Biol. Med.
Repeated exposure to far infrared ray attenuates acute restraint stress in mice via inhibition of JAK2/STAT3 signaling pathway by induction of glutathione peroxidase-1
Neurochem. Int.
Bcl-2 family: life-or-death switch
FEBS Lett.
Phosphoproteomic analysis of the striatum from pleiotrophin knockout and midkine knockout mice treated with cocaine reveals regulation of oxidative stress-related proteins potentially underlying cocaine-induced neurotoxicity and neurodegeneration
Toxicology
Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism
Neurochem. Int.
Seizures associated with recreational drug abuse
Neurology
Neurobiological correlates of alpha-tocopherol antiepileptogenic effects and microRNA expression modulation in a rat model of kainate-induced seizures
Mol. Neurobiol.
Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors
Ann. Neurol.
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Huynh Nhu Mai and Yoon Hee Chung have contributed equally to this work.