title: Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β.
abstract: The incidence of ischemic stroke is significantly increased in postmenopausal women. However, the neuroprotective effects of estrogen replacement therapy (ERT) against stroke remain controversial, and the role of astrocytes in ERT has rarely been explored. In this study, we investigated the effects of estrogen and selective estrogen receptor (ER) agonists on astrocytes activation and neuronal apoptosis in mice under conditions of cell culture oxygen and glucose deprivation and reperfusion (OGD-R), and global cerebral ischemia (GCI). We demonstrated that hippocampal astrocytes primarily express ERβ. In astrocytes, 2.5-20 nM 17β-estradiol (E2) or 10 nM DPN (ERβ agonist) not 10 nM PPT (ERα agonist), significantly increased GFAP expression. And 10 nM E2, DPN or E2+MPP (ERα antagonist), but not PPT or E2+PHTPP (ERβ antagonist), significantly reduced neuronal apoptosis following the subjection of astrocyte and neuronal cocultures to OGD-R. We also found that either 50 μg/kg E2 or 8 mg/kg DPN replacement (3 weeks) significantly increased GFAP expression and reduced GCI-induced neuronal apoptosis in hippocampal CA1 region of ovariectomized mice. These results indicate that estrogen-induced neuroprotection against ischemia-reperfusion injury involves activation of astrocytes via ERβ. Thus, the discovery and design of astrocyte-selective ERβ modulators may offer a new strategy for ERT of ischemic stroke.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.|Department of Anesthesiology, General Hospital of Chinese PLA Beijing Command, Beijing 100700, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Guo
authors.affiliation: First Affiliated Hospital to Chinese PLA General Hospital, Beijing 100048, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Anqi
authors.initials: A
authors.lastname: Yin
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wugang
authors.initials: W
authors.lastname: Hou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D053148:Caspase 3