title: Indirubin-3-Oxime Prevents H2O2-Induced Neuronal Apoptosis via Concurrently Inhibiting GSK3β and the ERK Pathway.
abstract: Oxidative stress-induced neuronal apoptosis plays an important role in many neurodegenerative disorders. In this study, we have shown that indirubin-3-oxime, a derivative of indirubin originally designed for leukemia therapy, could prevent hydrogen peroxide (H2O2)-induced apoptosis in both SH-SY5Y cells and primary cerebellar granule neurons. H2O2exposure led to the increased activities of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) in SH-SY5Y cells. Indirubin-3-oxime treatment significantly reversed the altered activity of both the PI3-K/Akt/GSK3β cascade and the ERK pathway induced by H2O2. In addition, both GSK3β and mitogen-activated protein kinase inhibitors significantly prevented H2O2-induced neuronal apoptosis. Moreover, specific inhibitors of the phosphoinositide 3-kinase (PI3-K) abolished the neuroprotective effects of indirubin-3-oxime against H2O2-induced neuronal apoptosis. These results strongly suggest that indirubin-3-oxime prevents H2O2-induced apoptosis via concurrent inhibiting GSK3β and the ERK pathway in SH-SY5Y cells, providing support for the use of indirubin-3-oxime to treat neurodegenerative disorders caused or exacerbated by oxidative stress.
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Lin
authors.affiliation: Ningbo Xiaoshi High School, Ningbo, 315010, China.
authors.forename: Linlu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hong Kong SAR, China.
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hong Kong SAR, China.
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.affiliation: The Affiliated Yinzhou Hospital, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Hongya
authors.initials: H
authors.lastname: Sun
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine and New Drug Research, College of Pharmacy, Jinan University, Guangdong, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
authors.forename: Mingyuen
authors.initials: M
authors.lastname: Lee
authors.affiliation: Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China.
authors.forename: Wahkeung
authors.initials: W
authors.lastname: Tsim
authors.affiliation: Ningbo Xiaoshi High School, Ningbo, 315010, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Su
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China. cuiwei@nbu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hong Kong SAR, China. bcyfhan@polyu.edu.hk.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China. wangqinwen@nbu.edu.cn.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007211:Indoles; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases; C027185:indirubin
keywords: ERK; GSK3β; H2O2; Indirubin-3-oxime; PI3-K