Phytoestrogen Beta-Ecdysterone Protects Pc12 Cells Against Mpp+-Induced Neurotoxicity In Vitro: Involvement Of Pi3k-Nrf2-Regulated Pathway

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 beta-ecdysterone (beta-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 beta-Ecd is able to protect MPP+-induced oxidative stress and apoptosis in PC12 cells in a concentration-dependent manner. beta-Ecd increased the Akt kinase activity and the Akt signaling pathways, including glycogen synthase kinase 3-beta inactivation, nuclear translocation of Nrf2, upregulation of HO-1 expression, but without affecting activity of both NF-kappa B and calpain. Enhancement of antioxidant response element (ARE) promoter-driven luciferase activity by beta-Ecd correlated with the blockade of oxidative stress. Antioxidative effects of beta-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 beta-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 beta-Ecd may be a potential candidate for further preclinical study aimed at the treatment of PD.