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. 2013:2013:196028.
doi: 10.1155/2013/196028. Epub 2013 Jun 19.

Metabotropic glutamate receptors for Parkinson's disease therapy

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Metabotropic glutamate receptors for Parkinson's disease therapy

Fabrizio Gasparini et al. Parkinsons Dis. 2013.

Abstract

Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD.

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Figures

Figure 1
Figure 1
Schematic representation of ionotropic and metabotropic glutamate receptor subtypes, their intracellular function, and synaptic localization. AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, DAG: diacylglycerol, iGluR: ionotropic glutamate receptor, IP3: inositol (1,4,5)-triphosphate, MAPK: mitogen-activated protein kinase, mGluR: metabotropic glutamate receptor, NMDAR: N-methyl-d-aspartate receptor, PKC: protein kinase C, PLC: phospholipase C, PLD: phospholipase D (reproduced with permission from Novartis Pharma AG. 2008 Novartis).
Figure 2
Figure 2
Immunolocalisation of mGlu 1 and 5 receptors within rat brain parasagittal sections. Acb, nucleus accumbens; Hi, hippocampus; IC, inferior colliculus; LS, lateral septal nucleus; OT, olfactory tubercle; SC, superior colliculus; SpV, spinal trigeminal nuclei; Th, thalamus [84].

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