Validation of metabotropic glutamate-receptor type 5 as a target for the treatment of L-DOPA-induced dyskinesia in a macaque model of Parkinson´s disease

Objective/Rationale:
Metabotropic glutamate receptor type 5 (mGluR5) is abundantly expressed in striatal neurons, where it modulates the response to glutamatergic and dopaminergic inputs. Previous studies have shown that pharmacological antagonism of mGluR5 attenuates L-DOPA-induced dyskinesia (LID) in a pre-clinical model of Parkinson´s disease. This project aims at validating the antidyskinetic efficacy of a selective mGluR5 antagonist in a non-human primate model of LID.

Project Description:
A selective mGluR5 antagonist called MTEP will be tested in parkinsonian macaque pre-clinical models. We shall first find a dose of MTEP that can acutely reduce the severity of pre-existing LID (as induced by prior treatment with L-DOPA). We shall next determine whether the same dose of MTEP can inhibit the gradual development and long-term priming for dyskinesia as induced by chronic treatment with L-DOPA de novo. Finally, we shall verify whether MTEP can block maladaptive molecular changes induced by L-DOPA, such as the pronounced activation of intracellular signaling pathways and gene expression in striatal neurons.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will provide a comprehensive validation of a new, promising pharmacological treatment for LID, prompting the translation of preclinical findings to cliinical trials. L-DOPA is very effective in treating the signs and symptoms of Parkinson´s disease, but its utility is severely limited by the emergence of dyskinesia (abnormal involuntary movements) in the majority of the patients. The management of PD would be greatly improved if adjunct treatments were available to either prevent or alleviate dyskinesia when coadministered with L-DOPA. Among all the approaches for the treatment of LID proposed so far, mGluR5 antagonism offers particular advantages in terms of both tolerability and antiparkinsonian (neuroprotective) potential. The high expression of mGluR5 in striatal neurons renders it an ideal target to block abnormal molecular and synaptic responses that are believed to cause LID. Finding new and safe drugs that can prevent the complications of L-DOPA treatment will allow patients to experience the full Symptoms & Side Effects efficacy of L-DOPA even in the advanced stages of PD.

Anticipated Outcome:
The project will prove whether pharmacological antagonism of mGluR5 is a viable strategy to reduce the dyskinetic effects of L-DOPA without interfering with its therapeutic efficacy against parkinsonian motor symptoms.