β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38^MAPK–p53 Signaling Pathway

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• 作者：Zhi Pan ; Yingcai Niu ; Yini Liang ; Xiaojie Zhang ; Miaoxian Dong
• 关键词：β ; Ecdysterone ; Parkinson’s disease ; p38MAPK ; Apoptosis ; Mitochondrial membrane potential
• 刊名：Neurotoxicity Research
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：30
• 期：3
• 页码：453-466
• 全文大小：2,273 KB
• 刊物主题：Neurosciences; Neurology; Neurochemistry; Pharmacology/Toxicology; Neurobiology; Cell Biology;
• 出版者：Springer US
• ISSN：1476-3524
• 卷排序：30

文摘

Parkinson’s disease (PD) is a neurological disorder pathologically characterized by loss of dopaminergic neurons in the substantia nigra. No curative therapy is available for PD. We recently found that phytoestrogen β-ecdysterone (β-Ecd) is able to reduce MPP+-induced apoptosis in PC12 cells. This study investigated the potential of β-Ecd to protect against SH-SY5Y cell apoptosis induced by the PD-related neurotoxin 6-hydroxydopamine (6-OHDA) and the underlying mechanism for this cytoprotection. In the present study, pretreatment with β-Ecd significantly reduced 6-OHDA-induced apoptosis of SH-SY5Y cells by a mitochondria-dependent pathway, as indicated by downregulation of Bax and PUMA (p53 upregulated modulator of apoptosis) expression, suppressing ΔΨm loss, inhibiting cytochrome c release, and attenuating caspase-9 activation. Furthermore, we showed that the inhibition of p38 mitogen-activated protein kinase (p38MAPK)-dependent p53 promoter activity contributed to the protection of SH-SY5Y cells from apoptosis, which was validated by the use of SB203580 or p38β dominant negative (DN) mutants. Additionally, knock-down apoptosis signal-regulating kinase 1 (ASK1) by specific shRNA and blockade reactive oxygen species (ROS) by pharmacological inhibitor competently prevented β-Ecd-mediated inhibition of p38MAPK and ASK1 phosphorylation, respectively. These data provide the first evidence that β-Ecd protects SH-SY5Y cells against 6-OHDA-induced apoptosis, possibly through mitochondria protection and p53 modulation via ROS-dependent ASK1–p38MAPK pathways. The neuroprotective effects of β-Ecd make it a promising candidate as a therapeutic agent for PD.