Phytoestrogen β-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 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.

Zou Y ，Wang R ，Guo H ，Dong M ... -  《-》

DJ-1 regulating PI3K-Nrf2 signaling plays a significant role in bibenzyl compound 20C-mediated neuroprotection against rotenone-induced oxidative insult.

Oxidative stress is thought to be involved in the development of Parkinson's disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.

Zhang XL ，Yuan YH ，Shao QH ，Wang ZZ ，Zhu CG ，Shi JG ，Ma KL ，Yan X ，Chen NH ... -  《-》

Resveratrol Attenuates the Cytotoxicity Induced by Amyloid-β(1-42) in PC12 Cells by Upregulating Heme Oxygenase-1 via the PI3K/Akt/Nrf2 Pathway.

Hui Y ，Chengyong T ，Cheng L ，Haixia H ，Yuanda Z ，Weihua Y ... -  《-》

Synergistic protective effect of paeoniflorin and β-ecdysterone against rotenone-induced neurotoxicity in PC12 cells.

Liu H ，Yu C ，Xu T ，Zhang X ，Dong M ... -  《-》

Deprenyl prevents MPP(+)-induced oxidative damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression through the activation of PI3K/Akt and Erk.

Neuroprotection has been the focus of several current efforts to develop a strategy for the treatment of Parkinson's disease (PD). The B-type monoamine oxidase (MAO-B) inhibitor deprenyl (selegiline) is used clinically as a PD therapeutic agent, however, its cytoprotective mechanism has not yet been fully elucidated. In this study, we show that deprenyl upregulates the expression and activity of NAD(P)H: quinone oxidoreductase 1 (NQO1), attenuates the increase in the quinoprotein levels in 1-methyl-4-phenylpyridinium (MPP(+))-treated PC12 cells, and protects PC12 cells from oxidative damage. Deprenyl triggers the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway by increasing the nuclear translocation and DNA-binding activity of Nrf2. Both the antioxidant activity of deprenyl and its effect on NQO1 upregulation were greatly attenuated in Nrf2 siRNA transfected cells. The phosphorylation of extracellular regulating protein kinase (Erk) and Akt can be induced by the administration of 50μM deprenyl in PC12 cells, and the ability of deprenyl to enhance NQO1 expression and Nrf2 nuclear translocation is partly attenuated by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 and is almost completely attenuated by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002. The activation of Nrf2/ARE signaling by deprenyl in PC12 cells is independent of MAO-B inhibition. Altogether, our findings indicate that deprenyl protects PC12 cells exposed to MPP(+) resulting from oxidative stress via the Nrf2-mediated upregulation of NQO1 involving both the PI3K/Akt and Erk pathways.

Xiao H ，Lv F ，Xu W ，Zhang L ，Jing P ，Cao X ... -  《-》