mGlu receptors in the treatment of Parkinson's disease and L-DOPA-induced dyskinesia

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HighlightsTargeting specific mGluRs normalizes excessive glutamate/GABA transmission in PD and LID models.mGluR5 NAMs normalise biochemical and molecular changes underlying LID.mGluR5 NAMs show promising results in early clinical trials for the treatment of LID.Systemically active mGluR4 PAMs can potentiate the antiakinetic action of L-DOPA.The first-ever clinical trial of a mGluR4 PAM in PD is currently ongoing.Parkinson's disease (PD) is a neurodegenerative disorder characterized by typical motor features that result from dopamine (DA) depletion in the striatum. DA replacement therapy with L-DOPA is the most efficacious symptomatic treatment, but causes complications that limit its utility, in particular, L-DOPA-induced dyskinesia (LID). LID is primarily caused by pre-synaptic and post-synaptic changes in DA neurotransmission, although it also depends on altered glutamatergic transmission at several nodes of the cortico-basal ganglia-thalamocortical network. The important functional interplay between dopaminergic and glutamatergic systems has stimulated an interest in metabotropic glutamate receptors (mGluRs) as potential therapeutic targets in PD and LID. We here review the antiparkinsonian and antidyskinetic potential of modulating group I, II, and III mGluRs in several preclinical models of PD. We also provide an update on clinical trials evaluating mGluR5 or mGluR4 ligands in PD.

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