title: Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease.
abstract: The etiology of Parkinson's disease remains poorly understood, and current treatment options do not slow disease progression. Recently, chemical (thrombin) preconditioning (TPC) was found to be protective in a 6-hydroxydopamine (6-OHDA) model of the disease. It is important to understand the mechanisms behind these thrombin-induced protective effects. The current study was conducted in the rat to determine whether the protective effects of TPC are mediated via activation of protease-activated receptors (PARs). Preconditioning with specific local infusion of agonist peptides for PAR-1 and PAR-4 3 days before unilateral 6-OHDA administration (10 microg into the medial forebrain bundle) was tested. In addition, co-administration of a PAR-1 antagonist with TPC was examined. In a neurobehavioral assessment battery, PAR-1 agonist preconditioning provided protection in a vibrissae-elicited forelimb placing test, a forelimb-use asymmetry test, and a corner turn test. In addition, inclusion of a PAR-1 antagonist prevented the protective effects elicited by TPC. In contrast to the effects of the PAR-1 agonist, PAR-4 agonist preconditioning afforded no such protection. Indeed, in a lower-dose model of 6-OHDA (5 microg), PAR-4 preconditioning significantly increased behavioral deficits. These results indicate that the protective effects of TPC in this model are mediated through PAR-1 activation. Neither the effects of PAR-1 nor TPC on later 6-OHDA-induced behavioral deficits appeared to be mediated through (DA) content sparing. Further mechanistic studies on the actions of PAR-1 and PAR-4 as detrimental in experimental models of Parkinson's disease are warranted.
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cannon
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.forename: Timothy
authors.initials: T
authors.lastname: Schallert
authors.forename: Ya
authors.initials: Y
authors.lastname: Hua
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
authors.forename: Guohua
authors.initials: G
authors.lastname: Xi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D005552:Forelimb / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000517:prevention & control* / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000502:physiology*; D018179:Receptors, Thrombin / Q000378:metabolism; D013565:Sympatholytics; D013917:Thrombin / Q000502:physiology*; D014738:Vibrissae / Q000502:physiology
chemical_list: D002395:Catecholamines; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013565:Sympatholytics; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D013917:Thrombin; C112908:protease-activated receptor 4; D006719:Homovanillic Acid