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Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β
Hu S.1,2,3; Cui W.1,2; Zhang Z.3; Mak S.1,2; Xu D.1,2; Li G.4; Hu Y.5; Wang Y.3; Lee M.5; Tsim K.W.6; Han Y.1,2
2015
Source PublicationJournal of Molecular Neuroscience
ISSN8958696
Volume57Issue:4Pages:561–570
Abstract

Indirubin-3-oxime (I3O), a synthetic derivative of indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. GSK3β inhibitors but not CDK5 inhibitors reduced the neurotoxicity induced by 6OHDA. Moreover, the activation of GSK3β was observed after 6OHDA treatment. Furthermore, 6OHDA substantially decreased the transcriptional activity of myocyte enhancer factor 2D (MEF2D), a transcription factor that plays an important role in dopaminergic neuron survival, and reduced nuclear localized MEF2D expression. Interestingly, indirubin-3-oxime and GSK3β inhibitors prevented 6OHDA-induced dysregulation of MEF2D. In addition, short hairpin RNA-mediated decrease of MEF2D expression significantly abolished the neuroprotective effects of indirubin-3-oxime. Collectively, our results strongly suggested that indirubin-3-oxime prevented 6OHDA-induced neurotoxicity via activating MEF2D, possibly through the inhibition of GSK3β. In view of the capability of indirubin-3-oxime to cross the blood–brain barrier, our findings further indicated that indirubin-3-oxime might be a novel drug candidate for neurodegenerative disorders, including Parkinson’s disease in particular.

Keyword6ohda Gsk3β Indirubin-3-oxime Mef2d Neuroprotection Parkinson’s Disease
DOI10.1007/s12031-015-0638-y
URLView the original
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Neurosciences & Neurology
WOS SubjectBiochemistry & Molecular Biology ; Neurosciences
WOS IDWOS:000365026000014
The Source to ArticleScopus
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Cited Times [WOS]:16   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorHan Y.
Affiliation1.Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
2.The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
3.Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
4.National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou, China
5.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
6.Division of Life Science, Center for Chinese Medicine and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China
Recommended Citation
GB/T 7714
Hu S.,Cui W.,Zhang Z.,et al. Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β[J]. Journal of Molecular Neuroscience,2015,57(4):561–570.
APA Hu S..,Cui W..,Zhang Z..,Mak S..,Xu D..,...&Han Y..(2015).Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β.Journal of Molecular Neuroscience,57(4),561–570.
MLA Hu S.,et al."Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β".Journal of Molecular Neuroscience 57.4(2015):561–570.
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