Abstract |
Glycogen synthase kinase-3beta (GSK-3beta) is closely involved in neuronal apoptosis and pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease. However, whether GSK-3beta mediates apoptosis of dopaminergic neurons in Parkinson's disease remains elusive. In this study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP)-induced Parkinsonism models, we investigated whether MPTP induces apoptosis of dopaminergic neurons through a GSK-3beta-dependent pathway. MPTP caused a rapid activation of GSK-3beta, evidenced by the decrease in level of phospho-Ser9 of GSK-3beta and the increase in level of phospho-Ser396 of tau, a known GSK-3beta substrate. Blockage of GSK-3beta activity by its two specific inhibitors, indirubin-3'-oxime and AR-A014418, prevented dopaminergic neurons from MPTP-induced apoptosis. Additionally, inhibition of GSK-3beta activity restored the depletion of striatal dopamine and ameliorated behavioral impairments caused by MPTP. These results indicate that GSK-3beta is a critical intermediate of MPTP neurotoxicity, and inhibition of GSK-3beta may provide a novel strategy to treat Parkinson's disease.
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Authors | Wenya Wang, Yi Yang, Chunyi Ying, Wenming Li, Haolan Ruan, Xiaonan Zhu, Yan You, Yifan Han, Ruzhu Chen, Yizheng Wang, Mingtao Li |
Journal | Neuropharmacology
(Neuropharmacology)
Vol. 52
Issue 8
Pg. 1678-84
(Jun 2007)
ISSN: 0028-3908 [Print] England |
PMID | 17517424
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Indoles
- Oximes
- Thiazoles
- indirubin-3'-monoxime
- tau Proteins
- N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
- Urea
- Tyrosine 3-Monooxygenase
- Glycogen Synthase Kinase 3
- Dopamine
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Topics |
- Analysis of Variance
- Animals
- Apoptosis
(drug effects)
- Corpus Striatum
(pathology)
- Disease Models, Animal
- Dopamine
(metabolism)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Freezing Reaction, Cataleptic
(drug effects)
- Glycogen Synthase Kinase 3
(metabolism)
- Indoles
(pharmacology)
- MPTP Poisoning
(pathology, physiopathology)
- Male
- Mice
- Mice, Inbred C57BL
- Neurons
(drug effects)
- Oximes
(pharmacology)
- Thiazoles
(pharmacology)
- Tyrosine 3-Monooxygenase
(metabolism)
- Urea
(analogs & derivatives, pharmacology)
- tau Proteins
(metabolism)
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