title: β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38(MAPK)-p53 Signaling Pathway.
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 (p38(MAPK))-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 p38(MAPK) 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-p38(MAPK) pathways. The neuroprotective effects of β-Ecd make it a promising candidate as a therapeutic agent for PD.
authors.affiliation: Center for New Medicine Research, Changchun University of Chinese Medicine, Changchun, 130117, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Pan
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, Jianhua District, Qiqihar, 161006, China.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Niu
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, Jianhua District, Qiqihar, 161006, China.
authors.forename: Yini
authors.initials: Y
authors.lastname: Liang
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, Jianhua District, Qiqihar, 161006, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, Jianhua District, Qiqihar, 161006, China. dmx1969@126.com.
authors.forename: Miaoxian
authors.initials: M
authors.lastname: Dong
mesh_terms: D000978:Antiparkinson Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004441:Ecdysterone / Q000494:pharmacology*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D016627:Oxidopamine / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004441:Ecdysterone; D016627:Oxidopamine; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: Apoptosis; Mitochondrial membrane potential; Parkinson’s disease; p38MAPK; β-Ecdysterone