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.
Footnotes
-
This work was supported by National Institutes of Health (NIH) grants R01-NS36654 and NS39419 (to S.F.T.), R21-ES012315 (to G.W.M.), U54-ES012068 (to G.W.M.) as part of the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER), a pilot grant from the CCPDER (to S.F.T.), NARSAD (to S.F.T.), the Michael J. Fox Foundation (to S.F.T.), the Georgia Tech Foundation (to K.D.P.), NIH fellowships F30-NS530062 (to C.E.H.) and F32-ES013457 (to J.R.R.), NIH grant K08-NS048858 (to J.G.G.), NIH grant T32-ES012879 (to W.M.C.), and a Cotzias Fellowship from the American Parkinson Disease Association (to J.G.G.).
-
S.F.T is a coinventor on patent-pending technology involving PAR1.
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
-
doi:10.1124/mol.107.038158.
-
ABBREVIATIONS: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PAR1, protease-activated receptor 1; HPLC, high-performance liquid chromatography; BMS-200261, trans-cinnamoyl-p-fluoro-Phe-p-guanidino-Phe-Leu-Arg-Arg-NH2; MPP+, 1-methyl-4-phenylpyridinium; WIN 35,428, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane; TBS, Tris-buffered saline; ANOVA, analysis of variance; DAT, dopamine transporter; TH, tyrosine hydroxylase; PCR, polymerase chain reaction; CNS, central nervous system; MMP1, matrix metalloprotease-1; GFAP, glial fibrillary acidic protein; WT, wild type; ERK, extracellular signal-regulated kinase.
-
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received May 15, 2007.
- Accepted June 27, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
