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

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.
AuthorsWenya Wang, Yi Yang, Chunyi Ying, Wenming Li, Haolan Ruan, Xiaonan Zhu, Yan You, Yifan Han, Ruzhu Chen, Yizheng Wang, Mingtao Li
JournalNeuropharmacology (Neuropharmacology) Vol. 52 Issue 8 Pg. 1678-84 (Jun 2007) ISSN: 0028-3908 [Print] England
PMID17517424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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