Pathophysiological clues to therapeutic applications of glutamate mGlu5 receptor antagonists in levodopa-induced dyskinesia
Section snippets
Theories on pathophysiology and formation of levodopa-induced dyskinesia
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNc), giving rise to bradykinesia, rigidity and tremor as its hallmark clinical signs. Dopamine replacement therapy with levodopa (L-DOPA) comprises the mainstay of symptomatic treatment for PD (Cotzias et al., 1967). L-DOPA effectively mitigates main motor manifestations of PD, at the expense of extra-CNS decarboxylation into dopamine leading to
Role of glutamatergic transmission in LID pathophysiology
The above-mentioned mechanisms together constitute an oversimplified view of LID pathophysiology. Formation and chronicity of LID is known to result from the interplay of a complex network of neurotransmitters, consisting of dopamine and glutamate transmission, GABAergic transmission, enkephalins and opioids (Bastide et al., 2015; Cerri et al., 2017). For example, long term potentiation and depression (LTP and LTD) in postsynaptic potential in believed to be mainly due to aberrant glutamate
Glutamate receptors in striatum and implications in LID pathophysiology
There are two families of glutamate receptors: first, glutamate ionotropic receptors (iGlu), which are designated after their high-affinity ligands: NMDA, GluN, AMPA, GluA, and kainite, GluK, respectively, and second, glutamate metabotropic receptors (mGlu), which are members of group C family of G-protein coupled receptors (GPCRs) and are further classified into three groups:
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Group I mGlu receptors, including mGlu1 and mGlu5 receptors which are coupled to Gq, which activates phospholipase C,
Future avenues on therapeutic applications
Although research on synthesized selective glutamate mGlu5 receptor antagonists has been quite successful, the main limitation is identification of highly selective compounds (Johnson et al., 2009). Until recently, most studies have investigated the effects of mGlu5 receptor antagonists on motor complications of levodopa and overlooked the potential positive or negative effects on non-motor symptoms, importantly the cognitive function (Matosin et al., 2018). Moreover, evidence is accumulating
Funding
The authors have no financial interest to disclose.
Conflict of interest
The authors declare no conflict of interest. This research did not involve Human Participants and/or Animals.
Financial disclosure/conflict of interest
Authors do not have any potential conflict of interest or funding source to disclose.
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2022, Neurochemistry InternationalCitation Excerpt :Data collected from both in vitro and in vivo studies indicate that mGluRs and subtypes possess desirable characteristics that possess a huge impact on the neurodegeneration process during PD (Bruno et al., 2017; Ribeiro et al., 2017). For instance, neuroinflammation can be regulated via modulation of degradation of mGluR5 through the lysosome-dependent pathway shown in HEK293T cells as well as in rodents (Zhang et al., 2021), and mGluR5 antagonists can also be targeted for the treatment of LID (Pourmirbabaei et al., 2019). Modulation of mGluR2 via LY-487,379 (positive allosteric modulator) has shown antipsychotic and anti-dyskinetic effects in the MPTP-lesioned primate model, and it also decreases the global parkinsonian score by approximately 15%, which in turn, cause an increase in the anti-parkinsonian effect of L-DOPA (Sid-Otmane et al., 2020).
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2022, Neurobiology of DiseaseCitation Excerpt :Thus, mGluR5s potentiate the effect of direct pathway in the basal ganglia (Voulalas et al., 2005) suggesting that antagonizing mGluR5s might reduce glutamate hyperexcitability and involuntary movements associated with LID. Pre-clinical and clinical evidence support this idea, showing that mGluR5 antagonism attenuates both the acute and the long-term effects of L-DOPA in inducing involuntary movements; these behavioral effects are accompanied by a normalization of molecular and neurochemical correlates of LID (for review, see (Pourmirbabaei et al., 2019) and (Sebastianutto and Cenci, 2018)). In dystonia, negative allosteric modulation of mGluR5 receptors has been shown to normalize dysfunctional cholinergic activity in a model of TOR1A dystonia (Sciamanna et al., 2014) and reverse synaptic plasticity deficits in two distinct genetic models of dystonia, TOR1A and GNAL (Martella et al., 2021).
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2021, NeuroToxicologyCitation Excerpt :By blocking the abnormal glutamate signaling, they are able to provide relief in motor symptoms of PD (Greenamyre and O’brien, 1991). Several studies have demonstrated that NMDA receptor antagonists such as Amantadine can reduce Parkinsonian rigidity induced by dopamine receptor antagonists suggesting that their use, along with present treatment, can improve the efficacy and tolerability of dopaminergic therapies (Fox et al., 2017; Pourmirbabaei et al., 2019; Uitti et al., 1996). Adamantine works as non-competitive antagonist at the phencyclidine (PCP) site within the NMDA-receptor (Crosby et al., 2003a), It also enhances release of dopamine from nerve terminals and delay its re-uptake (Mizoguchi et al., 1994; Takahashi et al., 1996).
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