Indirubin-3-Oxime Effectively Prevents 6OHDA-Induced Neurotoxicity in PC12 Cells via Activating MEF2D Through the Inhibition of GSK3β

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• 作者：Shengquan Hu ; Wei Cui ; Zaijun Zhang ; Shinghung Mak…
• 关键词：Parkinson’s disease ; Indirubin ; 3 ; oxime ; MEF2D ; GSK3β ; 6OHDA ; Neuroprotection
• 刊名：Journal of Molecular Neuroscience
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：57
• 期：4
• 页码：561-570
• 全文大小：1,169 KB
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• 作者单位：Shengquan Hu (1) (2) (3)
  Wei Cui (1) (2)
  Zaijun Zhang (3)
  Shinghung Mak (1) (2)
  Daping Xu (1) (2)
  Gang Li (4)
  Yuanjia Hu (5)
  Yuqiang Wang (3)
  Mingyuen Lee (5)
  Karl Wahkeung Tsim (6)
  Yifan Han (1) (2)
  
  1. 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
  
• 刊物主题：Neurosciences; Neurochemistry; Cell Biology; Proteomics; Neurology;
• 出版者：Springer US
• ISSN：1559-1166

文摘

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. Keywords Parkinson’s disease Indirubin-3-oxime MEF2D GSK3β 6OHDA Neuroprotection