n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and indirubin-3--monoxime

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.

Topics: Analysis of Variance; Animals; Apoptosis; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Freezing Reaction, Cataleptic; Glycogen Synthase Kinase 3; Indoles; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neurons; Oximes; tau Proteins; Thiazoles; Tyrosine 3-Monooxygenase; Urea