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β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38MAPK–p53 Signaling Pathway

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Abstract

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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China Grant 81373629 awarded to Miaoxian Dong. We thank Dr. Rongtian Wang for critical comments on the manuscript and Tianjiao Xu for secretarial help.

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Authors and Affiliations

  1. Center for New Medicine Research, Changchun University of Chinese Medicine, Changchun, 130117, China

    Zhi Pan

  2. The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, Jianhua District, Qiqihar, 161006, China

    Yingcai Niu, Yini Liang, Xiaojie Zhang & Miaoxian Dong

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  1. Zhi Pan
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Correspondence to Miaoxian Dong.

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Xiaojie Zhang and Miaoxian Dong have shared senior authorship.

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Pan, Z., Niu, Y., Liang, Y. et al. β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38MAPK–p53 Signaling Pathway. Neurotox Res 30, 453–466 (2016). https://doi.org/10.1007/s12640-016-9631-7

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