Journal
JOURNAL OF NEURAL TRANSMISSION
Volume 125, Issue 8, Pages 1225-1236Publisher
SPRINGER WIEN
DOI: 10.1007/s00702-018-1846-8
Keywords
Glutamatergic receptors; L-DOPA-induced dyskinesia; Pharmacological targets; Preclinical studies
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Funding
- Umberto Veronesi Foundation
- Progetto di Ricerca di Interesse Nazionale [PRIN2015FNWP34]
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Overactivation of the glutamatergic synapse leading to maladaptive synaptic plasticity in the basal ganglia is a well-demonstrated process involved in the onset of l-DOPA-induced dyskinesia (LID). Changes in glutamate release are paralleled by compensatory modifications of the expression and/or synaptic localization of both ionotropic and metabotropic glutamate receptors (mGluRs). Accordingly, compounds targeting N-methyl-d-aspartate glutamate receptors (NMDARs) and specific subtypes of metabotropic glutamate receptors (mGluR4 and mGluR5) have been tested both in preclinical and clinical studies. At present, amantadine, a low-affinity non-competitive NMDAR antagonist, represents the only recommended add-on agent with a moderate anti-dyskinetic activity. The present review describes recent advances in basic research, preclinical and early clinical studies in the attempt of identifying innovative strategies for an accurate modulation of both pre- and postsynaptic glutamate receptors to reduce the severity of LID. Even if a complete understanding of LID molecular bases is still lacking, several compounds demonstrated an anti-dyskinetic activity in preclinical and early clinical studies. These results indicate that modulation of the glutamatergic system remains one of the most promising pharmacological strategies in the field.
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