GPER1 mediates estrogen-induced neuroprotection against oxygen-glucose deprivation in the primary hippocampal neurons.
It is well-known that the neuroprotective effects of estrogen have potential in the prevention and amelioration of ischemic and degenerative neurological disorders, while the underlying mechanisms for estrogen actions are undefined. As an important mediator for the non-genomic functions of estrogen, GPER1 (G Protein-coupled Estrogen Receptor 1) has been suggested to involve in the beneficial roles of estrogen in neural cells. Here our studies on primary hippocampal neurons have focused on GPER1 in an in vitro model of ischemia using oxygen-glucose deprivation (OGD). GPER1 expression in the primary hippocampal neurons was stimulated by the OGD treatments. Both E2 (estradiol) and E2-BSA (membrane impermeable estradiol by covalent conjugation of bovine serum albumin) attenuated OGD-induced cell death in primary cultures of hippocampal neurons. Importantly, this membrane-mediated estrogen function requires GPER1 protein. Knocking down of GPER1 diminished, while overexpression of GPER1 potentiated, the protective roles of E2/E2-BSA following OGD. Additionally, the downstream mechanisms employed by membrane-associated estrogen signaling were found to include PI3K/Akt-dependent Ask1 inhibition in the primary hippocampal neurons. Overall, these research results could enhance our understanding of the neuroprotective actions for estrogen, and provide a new therapeutic target for improving stroke outcome and ameliorating degenerative neurological diseases.
Department of Neurosurgery, Wuhan General Hospital of Guangzhou Military Command of Chinese PLA, Wuhan 430070, Hubei Province, China; Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Baqiao District, Xi'an 710038, Shaanxi Province, China.
Tian-Zhi
TZ
Zhao
Department of Aerospace Biodynamics, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Fei
F
Shi
Department of Neurology, Chinese PLA No. 451 Hospital, Xi'an 710054, Shaanxi Province, China.
Jun
J
Hu
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Baqiao District, Xi'an 710038, Shaanxi Province, China. Electronic address: shimihe@sina.com.
Shi-Ming
SM
He
Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Baqiao District, Xi'an 710038, Shaanxi Province, China. Electronic address: qiandingqd@sina.com.
Qian
Q
Ding
Department of Neurosurgery, Wuhan General Hospital of Guangzhou Military Command of Chinese PLA, Wuhan 430070, Hubei Province, China. Electronic address: liantingmam@126.com.
Lian-Ting
LT
Ma
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D004958:Estradiol; D004967:Estrogens; D005947:Glucose; D048848:MAP Kinase Kinase Kinase 5; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D012710:Serum Albumin, Bovine; C532507:GPER1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C482859:Map3k5 protein, mouse
G Protein-coupled Estrogen Receptor 1; PI3 kinase; estrogen; ischemia; non-genomic estrogen signaling; oxygen-glucose deprivation