Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease

被引:24
作者
Cannon, Jason R.
Keep, Richard F.
Schallert, Timothy
Hua, Ya
Richardson, Rudy J.
Xi, Guohua
机构
[1] Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA
[4] Univ Texas, Dept Psychol, Austin, TX 78712 USA
[5] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA
关键词
6-hydroxydopamine; Parkinson's; thrombin preconditioning; protease-activated receptor; protease-activated receptor-1; protease-activated receptor-4;
D O I
10.1016/j.brainres.2006.07.094
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 mu g 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 mu g), 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 dopamine (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. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:177 / 186
页数:10
相关论文
共 58 条
[1]   Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor [J].
Andrade-Gordon, P ;
Mayanoff, BE ;
Derian, CK ;
Zhang, HC ;
Addo, MF ;
Darrow, AL ;
Eckardt, AJ ;
Hoekstra, WJ ;
McComsey, DF ;
Oksenberg, D ;
Reynolds, EE ;
Santulli, RJ ;
Scarborough, RM ;
Smith, CE ;
White, KB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12257-12262
[2]   Brain iron pathways and their relevance to Parkinson's disease [J].
Berg, D ;
Gerlach, M ;
Youdim, MBH ;
Double, KL ;
Zecca, L ;
Riederer, P ;
Becker, G .
JOURNAL OF NEUROCHEMISTRY, 2001, 79 (02) :225-236
[3]   Thrombin preconditioning provides protection in a 6-hydroxydopamine Parkinson's disease model [J].
Cannon, JR ;
Keep, RF ;
Hua, Y ;
Richardson, RJ ;
Schallert, T ;
Xi, GH .
NEUROSCIENCE LETTERS, 2005, 373 (03) :189-194
[4]   Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia [J].
Carreño-Müller, E ;
Herrera, AJ ;
de Pablos, RM ;
Tomás-Camardiel, M ;
Venero, JL ;
Cano, J ;
Machado, A .
JOURNAL OF NEUROCHEMISTRY, 2003, 84 (05) :1201-1214
[5]   Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo:: Role of microglial NADPH oxidase [J].
Choi, SH ;
Lee, DY ;
Kim, SU ;
Jin, BK .
JOURNAL OF NEUROSCIENCE, 2005, 25 (16) :4082-4090
[6]   Thrombin induces nigral dopaminergic neurodegeneration in vivo by altering expression of death-related proteins [J].
Choi, SH ;
Lee, DY ;
Ryu, JK ;
Kim, J ;
Joe, EH ;
Jin, BK .
NEUROBIOLOGY OF DISEASE, 2003, 14 (02) :181-193
[7]  
Choi SH, 2003, J NEUROSCI, V23, P5877
[8]   PROTEASE-ACTIVATED RECEPTORS START A FAMILY [J].
COUGHLIN, SR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (20) :9200-9202
[9]   Proteinase-activated receptors:: novel mechanisms of signaling by serine proteases [J].
Déry, O ;
Corvera, CU ;
Steinhoff, M ;
Bunnett, NW .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 1998, 274 (06) :C1429-C1452
[10]   Structure-function analysis of protease-activated receptor 4 tethered ligand peptides - Determinants of specificity and utility in assays of receptor function [J].
Faruqi, TR ;
Weiss, EJ ;
Shapiro, MJ ;
Huang, W ;
Coughlin, SR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (26) :19728-19734