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

• Published in: Neuropharmacology Vol. 52; no. 8; pp. 1678 - 1684
• 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
• Language: English
• Published: Elsevier Ltd 01.06.2007
• Subjects: AR-A014418; Dopaminergic neurons; GSK-3β; Indirubin-3′-oxime; MPTP; Parkinson's disease; AR-A014418; Parkinson's disease; Indirubin-3′-oxime; 6-OHDA; SNc; i.p; Dopaminergic neurons; GSK-3β; FITC; PD; TH; CGNs; MPTP
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2007.03.017

Glycogen synthase kinase-3β (GSK-3β) is closely involved in neuronal apoptosis and pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease. However, whether GSK-3β 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-3β-dependent pathway. MPTP caused a rapid activation of GSK-3β, evidenced by the decrease in level of phospho-Ser9 of GSK-3β and the increase in level of phospho-Ser396 of tau, a known GSK-3β substrate. Blockage of GSK-3β activity by its two specific inhibitors, indirubin-3′-oxime and AR-A014418, prevented dopaminergic neurons from MPTP-induced apoptosis. Additionally, inhibition of GSK-3β activity restored the depletion of striatal dopamine and ameliorated behavioral impairments caused by MPTP. These results indicate that GSK-3β is a critical intermediate of MPTP neurotoxicity, and inhibition of GSK-3β may provide a novel strategy to treat Parkinson's disease.