PT  - JOURNAL ARTICLE
AU  - Cecily E. Hamill
AU  - W. Michael Caudle
AU  - Jason R. Richardson
AU  - Hongjie Yuan
AU  - Kurt D. Pennell
AU  - James G. Greene
AU  - Gary W. Miller
AU  - Stephen F. Traynelis
TI  - Exacerbation of Dopaminergic Terminal Damage in a Mouse Model of Parkinson's Disease by the G-Protein-Coupled Receptor Protease-Activated Receptor 1
AID  - 10.1124/mol.107.038158
DP  - 2007 Sep 01
TA  - Molecular Pharmacology
PG  - 653--664
VI  - 72
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/72/3/653.short
4100  - http://molpharm.aspetjournals.org/content/72/3/653.full
SO  - Mol Pharmacol2007 Sep 01; 72
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics