Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2597415 | Toxicology | 2008 | 14 Pages |
Abstract
Many studies showed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was widely used to produce Parkinson's disease (PD)-like models in animals can elicit apoptosis with increase of caspase activity via its neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+). Another pathway shown in MPTP-mediated nigrostriatal dopaminergic cell death involved the c-Jun-N-terminal kinases (JNKs) which are stress-activated protein kinases (SAPKs). Activation of the JNKs leads to the activation of transcription factors such as c-Jun that regulates its own expression. However, it is not known whether the activation of c-Jun is crucial in the stimulation of caspases leading to apoptosis observed in PD-like models. The aim of this study was to investigate the cellular expression and phosphorylation of c-Jun and the caspase-9 activity in rat injured with an intranigral injection of MPP+. Furthermore, we determined the effects of a cell-permeable peptide TAT-JBD, inhibiting selectively JNKs, on apoptosis markers and on the expression of tyrosine hydroxylase (TH). Our results showed that MPP+ induced not only an activation of c-Jun but also an early and robust stimulation of caspase-9 in midbrain of rats. Furthermore, a preliminary intravenous injection of TAT-JBD reduced the caspase-9 activation specifically induced by MPP+ suggesting a control of the JNKs pathway on the intrinsic way of apoptosis in MPP+-toxicity. However, the inhibition of the JNK pathway did not prevent TH inhibition, DNA fragmentation and Bad expression in MPP+-lesioned substantia nigra of rats. Therefore, the possibility of intervention on the JNK pathway as a therapeutic strategy in Parkinson's disease is questionable.
Keywords
SAPKJnk1-methyl-4-phenylpyridinium ionp-nitroanilineAPAf-1LEHDMPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinec-Jun N-terminal kinaseMAPKMPP+p-NARibosomal s6 kinaseapoptotic protease activating factor-1Akt/PKBParkinson's diseasesubstantia nigraTUNELtyrosine hydroxylasec-Junrat pheochromocytoma cell linePC12 cellsSH-SY5Y cellshuman neuroblastoma cellsRatNeuropeptideprotein kinase Bmitogen-activated protein kinaseStress-activated protein kinaseCaspase-9
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Authors
Stéphanie Pain, Laurence Barrier, Julie Deguil, Serge Milin, Alain Piriou, Bernard Fauconneau, Guylène Page,