title: Phytoestrogen β-Ecdysterone Protects PC12 Cells Against MPP+-Induced Neurotoxicity In Vitro: Involvement of PI3K-Nrf2-Regulated Pathway.
abstract: Epidemiological studies have strongly linked postmenopausal estrogens uptake with a reduced risk of developing Parkinson's disease (PD) in women. Estrogen replacement therapy may be beneficial in early PD. The aim of this study is to evaluate the hypothesis that the neuroprotective effects of phytoestrogen β-ecdysterone (β-Ecd) might mainly result from its antioxidant capability by the activation of the phosphoinositide-3-kinase (PI3K)-nuclear factor E2-related factor 2 (Nrf2)-regulated signaling pathway. We found that β-Ecd is able to protect MPP(+)-induced oxidative stress and apoptosis in PC12 cells in a concentration-dependent manner. β-Ecd increased the Akt kinase activity and the Akt signaling pathways, including glycogen synthase kinase 3-β inactivation, nuclear translocation of Nrf2, upregulation of HO-1 expression, but without affecting activity of both NF-κB and calpain. Enhancement of antioxidant response element (ARE) promoter-driven luciferase activity by β-Ecd correlated with the blockade of oxidative stress. Antioxidative effects of β-Ecd could be blocked by pharmacologic inhibition of the PI3K pathways with LY294002 or Nrf2 pathway with shRNA-mediated knockdown of Nrf2 but not by SP600125 (JNK inhibitor), SB203580 (p38-MAPK inhibitor), or PD98059 (ERK1/2 inhibitor). Together, our results indicate that the inducible effect of β-Ecd on HO-1 expression might be mediated, at least in part, by activating Akt kinase pathway and subsequent enhancement of Nrf2/ARE signaling pathway. In concert, these data suggest that β-Ecd may be a potential candidate for further preclinical study aimed at the treatment of PD.
authors.affiliation: *The Hub Laboratory and Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China; and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: *The Hub Laboratory and Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China; and.
authors.forename: Rongtian
authors.initials: R
authors.lastname: Wang
authors.affiliation: Medical Technology Department, Qiqihar Medical University, Qiqihar 161006, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: *The Hub Laboratory and Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China; and dmx1969@126.com.
authors.forename: Miaoxian
authors.initials: M
authors.lastname: Dong
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004441:Ecdysterone / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D020267:MPTP Poisoning / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D048789:Phytoestrogens / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D048789:Phytoestrogens; D017382:Reactive Oxygen Species; D004441:Ecdysterone; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D002154:Calpain
keywords: Nrf2; Parkinson’s disease; apoptosis; oxidative stress; β-ecdysterone