Ginsenoside Rg1 protection against β-amyloid peptide-induced neuronal apoptosis via estrogen receptor α and glucocorticoid receptor-dependent anti-protein nitration pathway.

Jiaying Wu, Zongfu Pan, Zhiqiang Wang, Wenjie Zhu, Yuanyuan Shen, Rong Cui, Jiazhen Lin, Hao Yu, Qiongque Wang, Jianchang Qian, Yongping Yu, Danyan Zhu, Yijia Lou

Index: Neuropharmacology 63(3) , 349-61, (2012)

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Abstract

Ginsenoside Rg1 (Rg1) acts as a neuroprotective agent against various insults, however, the underlying mechanism has not been fully elucidated yet. Here, we report that Rg1 protects primary rat cerebrocortical neurons against β-amyloid peptide₂₅₋₃₅ (Aβ₂₅₋₃₅) injury via estrogen receptor α (ERα) and glucocorticoid receptor (GR)-dependent anti-protein nitration pathway. In primary rat cerebrocortical neuron cultures under basal conditions, Rg1 leads to nuclear translocation of ERα and GR, induces related responsive gene PR, pS₂ and MKP-1, SGK transcription. Meantime, Rg1 also increases the basal level of ERK1/2 phosphorylation. In the presence of toxic level of Aβ₂₅₋₃₅, Rg1 maintains ERK1/2 phosphorylation, attenuates iNOS expression, NO production, and inhibits NF-κB nuclear translocation, protein nitration and cell death. The antiapoptotic effects of Rg1 via both ERα and GR were abolished by small interfering RNAs (siRNA). ERK1/2 phosphorylation inhibitor U0126 can block downstream iNOS expression and NO generation. Interestingly, the anti-protein nitration effect of Rg1 is well matched with ERα and GR activation, although its anti-ROS production effect is in an ERα- and GR-independent manner. These results suggest that Rg1 ameliorates Aβ₂₅₋₃₅-induced neuronal apoptosis at least in part by two complementary ERα- and GR-dependent downstream pathways: (1) upregulation of ERK1/2 phosphorylation followed by inhibiting iNOS expression, NO generation and protein tyrosine nitration. (2) reduction NF-κB nuclear translocation. These data provide new understanding into the mechanisms of Rg1 anti-apoptotic functions after Aβ₂₅₋₃₅ exposure, suggesting that ERα and GR-dependent anti-protein tyrosine nitration pathway might take an important role in the neuroprotective effect of Rg1.Copyright © 2012 Elsevier Ltd. All rights reserved.