GLUTAMATE RECEPTORS: TARGETS FOR PARKINSON?S DISEASE PHARMACOTHERAPY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to test the antiparkinsonian efficacy and neuroprotective effects of metabotropic glutamate receptor 5 (mGluR5) antagonist in the MPTP-treated monkey model of Parkinson's disease. Based on promising rodent studies showing evidence for mGluR5-mediated neuroprotection of midbrain dopaminergic neurons in MPTP-treated or mGluR5 knock out mice, we undertook a series of experiments aimed at testing the neuroprotective properties of the mGluR5 antagonist, MTEP, in rhesus monkeys treated chronically with low doses of MPTP. Using a combination of behavioral studies, functional brain imaging (PET imaging using the dopamine transporter ligand-18F-FECNT) and postmortem immunocytochemistry, our recent findings provided clear evidence for significant neuroprotection of the nigrostriatal dopaminergic system in MPTP-treated monkeys that received daily injection of mGluR5 antagonist, suggesting the potential neuroprotective properties of mGluR5 antagonist in Parkinson's disease. In another series of ongoing experiments, we are currently assessing the symptomatic antiparkinsonian efficacy of mGluR5 antagonist alone or in combination with A2A antagonist in MPTP-treated parkinsonian monkeys. Although these studies are not yet completed, we have some evidence that systemic administration of mGluR5 antagonist in MPTP-treated monkeys has significant antiparkinsonian effects. Experiments are in progress to assess the potential synergistic effects of mGluR5 and A2A antagonist in these animals, as recently shown in rat models of PD. These exciting findings should lead to strong preclinical evidence for the development of novel antiparkinsonian and neuroprotective therapies in Parkinson's disease.