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Thrombin induces nigral dopaminergic neurodegeneration in vivo by altering expression of death-related proteins.

Authors
Choi, SH; Lee, DY; Ryu, JK; Kim, J; Joe, EH; Jin, BK
Citation
Neurobiology of disease, 14(2):181-193, 2003
Journal Title
Neurobiology of disease
ISSN
0969-99611095-953X
Abstract
One week after intranigral injection of thrombin resulted in a dose-dependent loss of dopaminergic neurons (20-78%) in the rat substantia nigra (SN), as evidenced by tyrosine hydroxylase (TH) immunohistochemistry. This cell death was accompanied by localization of terminal deoxynucleotidyl transferase-mediated fluorecein UTP nick end labeling (TUNEL) staining within dopaminergic neurons, activation of caspase-3 and attenuation of dopaminergic neuronal cell death in the SN by the caspase inhibitor (zVAD-fmk), indicative of apoptosis. Furthermore, Western blot analyses and double-immunofluorescent staining showed activation of c-Jun N-terminal kinase (JNK) and p53, and a localization of p53 in the dopaminergic neurons in the SN after thrombin, respectively. Intriguingly, Western blot analyses demonstrated significant down-regulation of Bcl-2 protein, but no alteration in Bax protein expression in the SN after thrombin. Consistent with in vivo data, degeneration of dopaminergic neurons and colocalization of TUNEL and TH were observed in mesencephalic cultures, following treatment with thrombin. Cell death was almost completely abolished by the thrombin-specific inhibitor, hirudin. Thrombin receptor-activating peptides (TRAP-6 and-14) did not mimic the effects of thrombin, even at much higher (1,000 to 2,000-fold) concentrations, although expression of protease-activated receptor-1 (PAR-1) mRNA was detected using RT-PCR. Morphological evidence and molecular events in vivo and in vitro collectively suggest that thrombin induces apoptosis in dopaminergic neurons via non-PAR-1 receptors.
MeSH terms
AnimalsCell Death/drug effectsCell Death/physiologyCells, CulturedDopamine/metabolism*FemaleGene Expression Regulation/drug effects*Gene Expression Regulation/physiologyNerve Degeneration/chemically inducedNerve Degeneration/metabolism*Nerve Degeneration/pathologyProtein BiosynthesisRNA, Messenger/biosynthesisRatsRats, Sprague-DawleyReceptor, PAR-1/metabolismvSubstantia Nigra/drug effects*Substantia Nigra/metabolismSubstantia Nigra/pathologyThrombin/pharmacology*Thrombin/toxicity
PMID
14572441
Appears in Collections:
Journal Papers > Research Organization > Institute for Medical Sciences
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
조, 은혜진, 병관
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