RT Journal Article
SR Electronic
T1 Exacerbation of Dopaminergic Terminal Damage in a Mouse Model of Parkinson's Disease by the G-Protein-Coupled Receptor Protease-Activated Receptor 1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 653
OP 664
DO 10.1124/mol.107.038158
VO 72
IS 3
A1 Cecily E. Hamill
A1 W. Michael Caudle
A1 Jason R. Richardson
A1 Hongjie Yuan
A1 Kurt D. Pennell
A1 James G. Greene
A1 Gary W. Miller
A1 Stephen F. Traynelis
YR 2007
UL http://molpharm.aspetjournals.org/content/72/3/653.abstract
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