title: Ginsenoside Rg1 protection against β-amyloid peptide-induced neuronal apoptosis via estrogen receptor α and glucocorticoid receptor-dependent anti-protein nitration pathway.
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.
authors.affiliation: Division of Cardio-Cerebral Vascular and Hepatic Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Wu
authors.forename: Zongfu
authors.initials: Z
authors.lastname: Pan
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Rong
authors.initials: R
authors.lastname: Cui
authors.forename: Jiazhen
authors.initials: J
authors.lastname: Lin
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Qiongque
authors.initials: Q
authors.lastname: Wang
authors.forename: Jianchang
authors.initials: J
authors.lastname: Qian
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
authors.forename: Danyan
authors.initials: D
authors.lastname: Zhu
authors.forename: Yijia
authors.initials: Y
authors.lastname: Lou
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000187:drug effects*; D005260:Female; D036145:Ginsenosides / Q000494:pharmacology*; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D011247:Pregnancy; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D047628:Estrogen Receptor alpha; D036145:Ginsenosides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D020928:Mitogen-Activated Protein Kinases; C035054:ginsenoside Rg1