Indirubin-3-Oxime Prevents H2O2-Induced Neuronal Apoptosis via Concurrently Inhibiting GSK3β and the ERK Pathway
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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. H2O2 exposure 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.
KeywordsIndirubin-3-oxime H2O2 GSK3β PI3-K ERK
Analysis of variance
Cerebellar granule neurons
Extracellular signal-regulated kinase
Fetal bovine serum
Glycogen synthase kinase 3β
Mitogen-activated protein kinase
Reactive oxygen species
This work was supported by the Natural Science Foundation of Zhejiang Province (LY15H310007), Research Grants Council of Hong Kong (561011 & 15101014), the Applied Research Project on Nonprofit Technology of Zhejiang Province (2016C37110), the National Natural Science Foundation of China (U1503223, 81202150, 81471398), the Ningbo International Science and Technology Cooperation Project (2014D10019), Ningbo municipal innovation team of life science and health (2015C110026), Ningbo Natural Science Foundation (2015A610219), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, the State Education Ministry, and the K. C. Wong Magna Fund in Ningbo University.
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