%0 Journal Article
%T Metabotropic Glutamate Receptors for Parkinson's Disease Therapy
%A Fabrizio Gasparini
%A Th¨Śr¨¨se Di Paolo
%A Baltazar Gomez-Mancilla
%J Parkinson's Disease
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/196028
%X Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of ParkinsonĄŻs 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. 1. Introduction ParkinsonĄŻs disease (PD) is a chronic progressive neurodegenerative disorder of the central nervous system (CNS), characterised by a gradual loss of dopaminergic neurotransmission. Cardinal symptoms of PD include tremor, bradykinesia, and rigidity. Levodopa (L-DOPA) is considered the standard of care for providing symptomatic relief in PD [1]. However, long-term L-DOPA treatment leads to the appearance of motor complications in the majority of responding patients and severely affects their quality of life [2]. After 9 years of L-DOPA treatment, ~90% of PD patients experience dyskinesia [3]. The dyskinesia that develops is often a combination of choreic and dystonic abnormal involuntary movements, collectively termed L-DOPA-induced dyskinesia (PD-LID). Once PD-LID is established, increasing the L-DOPA dose typically worsens dyskinesia and this may prevent the use of L-DOPA at optimal doses required to control motor fluctuations. There are currently no licensed therapies for the treatment of PD-LID, although a number of clinical strategies are employed including adding dopamine agonists, monoamine oxidase inhibitors, adenosine (2A) receptor antagonists, catechol-O-methyl transferase inhibitors, and anticholinergic drugs as part of a L-DOPA-sparing
%U http://www.hindawi.com/journals/pd/2013/196028/