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Title: Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1.

Authors: Hamill, Cecily E; Caudle, W Michael; Richardson, Jason R; Yuan, Hongjie; Pennell, Kurt D; Greene, James G; Miller, Gary W; Traynelis, Stephen F

Published In Mol Pharmacol, (2007 Sep)

Abstract: Protease-activated receptor 1 (PAR1) is a G-protein-coupled receptor activated by serine proteases and expressed in astrocytes, microglia, and specific neuronal populations. We examined the effects of genetic deletion and pharmacologic blockade of PAR1 in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, a neurodegenerative disease characterized by nigrostriatal dopamine damage and gliosis. After MPTP injection, PAR1-/- mice showed significantly higher residual levels of dopamine, dopamine transporter, and tyrosine hydroxylase and diminished microgliosis compared with wild-type mice. Comparable levels of dopaminergic neuroprotection from MPTP-induced toxicity were obtained by infusion of the PAR1 antagonist, BMS-200261 into the right lateral cerebral ventricle. MPTP administration caused changes in the brain protease system, including increased levels of mRNA for two PAR1 activators, matrix metalloprotease-1 and Factor Xa, suggesting a mechanism by which MPTP administration could lead to overactivation of PAR1. We also report that PAR1 is expressed in human substantia nigra pars compacta glia as well as tyrosine hydroxylase-positive neurons. Together, these data suggest that PAR1 might be a target for therapeutic intervention in Parkinson's disease.

PubMed ID: 17596374 Exiting the NIEHS site

MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology; Animals; Disease Models, Animal; Dopamine/metabolism*; Factor Xa/metabolism; Guanidines/pharmacology; Immunohistochemistry; Male; Matrix Metalloproteinase 1/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroglia/drug effects; Neuroglia/pathology; Neurons/drug effects; Neurons/enzymology; Neurons/pathology; Oligopeptides/pharmacology; Parkinsonian Disorders/chemically induced; Parkinsonian Disorders/metabolism*; Parkinsonian Disorders/pathology; RNA, Messenger/metabolism; Receptor, PAR-1/antagonists & inhibitors*; Receptor, PAR-1/genetics; Receptor, PAR-1/metabolism; Substantia Nigra/drug effects; Substantia Nigra/metabolism; Substantia Nigra/pathology; Tyrosine 3-Monooxygenase/metabolism

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