EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages
EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages
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EGFR 介导黄芪甲苷 IV 诱导的 Nrf2 激活，以保护皮质神经元免受体外缺血/再灌注损伤。
DOI：
10.1016/j.bbrc.2015.01.002
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发表时间：
2015-02-13
影响因子：
3.1
通讯作者：
Wang, Qiong
中科院分区：
文献类型：
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作者：
Gu, Da-min;Lu, Pei-Hua;Wang, Qiong
本研究旨在探讨黄芪甲苷（AS-IV）对缺氧缺糖/复氧（OGD/R）诱导的小鼠皮层神经元损伤的保护作用，并探讨其信号转导机制。AS-IV通过减少活性氧（ROS）的积累，从而减轻氧化应激和神经元细胞死亡，对OGD/R产生显著的神经保护作用。我们发现，在皮质神经元中，AS-IV处理导致NF-E2相关因子2（Nrf 2）信号传导激活，通过Nrf 2 Ser-40磷酸化及其核定位以及抗氧化剂反应元件（ARE）调节基因的转录来证明：血红素加氧酶-1（HO-1）、NAD（P）H：醌氧化还原酶1（NQO-1）和硫氧还蛋白1（SRXN-1）。通过慢病毒shRNAs敲低Nrf 2可抑制AS-IV诱导的ARE基因转录，并消除其抗氧化和神经保护活性。此外，我们发现，AS-IV刺激肝素结合表皮生长因子（HB-EGF）的释放，以反式激活表皮生长因子受体（EGFR）在皮层神经元。阻断或沉默EGFR可阻止AS-IV激活Nrf 2，从而抑制AS-IV介导的抗OGD/R的抗氧化和神经保护活性。总之，AS-IV通过激活EGFR-Nrf 2信号通路保护皮质神经元免受OGD/R损伤。(C)2015 Elsevier Inc. All rights reserved.
In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. (C) 2015 Elsevier Inc. All rights reserved.