Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity

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...

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Published inNeuropharmacology Vol. 52; no. 8; p. 1678
Main Authors Wang, Wenya, Yang, Yi, Ying, Chunyi, Li, Wenming, Ruan, Haolan, Zhu, Xiaonan, You, Yan, Han, Yifan, Chen, Ruzhu, Wang, Yizheng, Li, Mingtao
Format Journal Article
LanguageEnglish
Published England 01.06.2007
Subjects
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
Male
Mice
Mice, Inbred C57BL
MPTP Poisoning - pathology
MPTP Poisoning - physiopathology
Neurons - drug effects
Oximes - pharmacology
tau Proteins - metabolism
Thiazoles - pharmacology
Tyrosine 3-Monooxygenase - metabolism
Urea - analogs & derivatives
Urea - pharmacology
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Summary: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.
ISSN:0028-3908