期刊
NEUROPHARMACOLOGY
卷 63, 期 3, 页码 349-361出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2012.04.005
关键词
beta-Amyloid; Receptor nuclear translocation; Ginsenoside Rg1; Protein tyrosine nitration; ERK1/2 phosphorylation
资金
- National Natural Sciences Foundation of China [30973600, 90813026, 81173135]
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 beta-amyloid peptide(25-35) (A beta(25-35)) injury via estrogen receptor alpha (ER alpha) and glucocorticoid receptor (GR)-dependent anti-protein nitration pathway. In primary rat cerebrocortical neuron cultures under basal conditions, Rg1 leads to nuclear translocation of ER alpha and GR, induces related responsive gene PR, pS(2) and MKP-1, SGK transcription. Meantime, Rg1 also increases the basal level of ERK1/2 phosphorylation. In the presence of toxic level of A beta(25-35), Rg1 maintains ERK1/2 phosphorylation, attenuates iNOS expression, NO production, and inhibits NF-kappa B nuclear translocation, protein nitration and cell death. The antiapoptotic effects of Rg1 via both ER alpha 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 ER alpha and GR activation, although its anti-ROS production effect is in an ER alpha- and GR-independent manner. These results suggest that Rg1 ameliorates A beta(25-35)-induced neuronal apoptosis at least in part by two complementary ER alpha- 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-kappa B nuclear translocation. These data provide new understanding into the mechanisms of Rg1 anti-apoptotic functions after A beta(25-35) exposure, suggesting that ER alpha and GR-dependent anti-protein tyrosine nitration pathway might take an important role in the neuroprotective effect of Rg1. (C) 2012 Elsevier Ltd. All rights reserved.
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