Icariside II, a novel phosphodiesterase 5 inhibitor, protects against H₂O₂-induced PC12 cells death by inhibiting mitochondria-mediated autophagy

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• 作者：Jianmei Gao ; Yuanyuan Deng ; Caixia Yin ; Yuangui Liu ; Wei Zhang ; Jingshan Shi and Qihai Gong
• 刊名：Journal of Cellular and Molecular Medicine
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：21
• 期：2
• 页码：375-386
• 全文大小：1141K
• ISSN：1582-4934

文摘

Oxidative stress is a major cause of cellular injury in a variety of human diseases including neurodegenerative disorders. Thus, removal of excessive reactive oxygen species (ROS) or suppression of ROS generation may be effective in preventing oxidative stress-induced cell death. This study was designed to investigate the effect of icariside II (ICS II), a novel phosphodiesterase 5 inhibitor, on hydrogen peroxide (H₂O₂)-induced death of highly differentiated rat neuronal PC12 cells, and to further examine the underlying mechanisms. We found that ICS II pre-treatment significantly abrogated H₂O₂-induced PC12 cell death as demonstrated by the increase of the number of metabolically active cells and decrease of intracellular lactate dehydrogenase (LDH) release. Furthermore, ICS II inhibited H₂O₂-induced cell death through attenuating intracellular ROS production, mitochondrial impairment, and activating glycogen synthase kinase-3β (GSK-3β) as demonstrated by reduced intracellular and mitochondrial ROS levels, restored mitochondrial membrane potential (MMP), decreased p-tyr216-GSK-3β level and increased p-ser9-GSK-3β level respectively. The GSK-3β inhibitor SB216763 abrogated H₂O₂-induced cell death. Moreover, ICS II significantly inhibited H₂O₂-induced autophagy by the reducing autophagosomes number and the LC3-II/LC3-I ratio, down-regulating Beclin-1 expression, and up-regulating p62/SQSTM1 and HSP60 expression. The autophagy inhibitor 3-methyl adenine (3-MA) blocked H₂O₂-induced cell death. Altogether, this study demonstrated that ICS II may alleviate oxidative stress-induced autophagy in PC12 cells, and the underlying mechanisms are related to its antioxidant activity functioning via ROS/GSK-3β/mitochondrial signalling pathways.