title: 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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 5025 Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Cecily E
authors.initials: CE
authors.lastname: Hamill
authors.forename: W Michael
authors.initials: WM
authors.lastname: Caudle
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Pennell
authors.forename: James G
authors.initials: JG
authors.lastname: Greene
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
chemical_list: D006146:Guanidines; C479887:N-cinnamoyl-4-fluorophenylalanyl-4-guanidinophenylalanyl-leucyl-arginyl-argininamide; D009842:Oligopeptides; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D015951:Factor Xa; D020781:Matrix Metalloproteinase 1; D004298:Dopamine; D010975:Platelet Aggregation Inhibitors