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

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.

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@article{Hamill2007ExacerbationOD, title={Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1.}, author={Cecily E Hamill and William Michael Caudle and Jason R. Richardson and Hongjie Yuan and Kurt D. Pennell and James G. Greene and Gary W. Miller and Stephen F Traynelis}, journal={Molecular pharmacology}, year={2007}, volume={72 3}, pages={653-64} }