title: EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Affiliated Yixing People's Hospital, Jiangsu University, Yixing, China.
authors.forename: Da-Min
authors.initials: DM
authors.lastname: Gu
authors.affiliation: Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China. Electronic address: lphty1_1@163.com.
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Affiliated Yixing People's Hospital, Jiangsu University, Yixing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Yixing People's Hospital, Jiangsu University, Yixing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Affiliated Yixing People's Hospital, Jiangsu University, Yixing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Clinical Laboratory, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.
authors.forename: Guo-Qian
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China. Electronic address: WangQiongprof1@126.com.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D012503:Saponins / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012503:Saponins; D014315:Triterpenes; C052064:astragaloside A; D066246:ErbB Receptors
keywords: Astragaloside IV; EGFR; Ischemia/reperfusion; Neuroprotection; Nrf2