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, 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.
Wang
Wenya
W
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Yang
Yi
Y
Ying
Chunyi
C
Li
Wenming
W
Ruan
Haolan
H
Zhu
Xiaonan
X
You
Yan
Y
Han
Yifan
Y
Chen
Ruzhu
R
Wang
Yizheng
Y
Li
Mingtao
M
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D020267:MPTP Poisoning / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D010091:Oximes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D010091:Oximes; D013844:Thiazoles; C474021:indirubin-3'-monoxime; D016875:tau Proteins; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D014446:Tyrosine 3-Monooxygenase; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine