title: Alleviation of ischaemia-reperfusion injury by endogenous estrogen involves maintaining Bcl-2 expression via the ERα signalling pathway.
abstract: The neuroprotective effects of estrogen against cerebral ischaemia have been confirmed by multiple basic and clinical studies. However, most of these studies used exogenous estrogen administered via different injection methods, and the neuroprotective effects of endogenous estrogen produced by ovaries during different phases of estrous cycle and the underlying mechanisms involved have rarely been explored. In this study, we first identified the stage of estrous cycle via vaginal smears and then measured serum estradiol levels at each phase via radioimmunoassay. We found that the estradiol level was highest in the proestrous and lowest in the diestrous. However, ovariectomy or treatment with the aromatase inhibitor letrozole significantly decreased estradiol levels compared to that of rats in diestrous. Western blotting showed that ovariectomy or letrozole treatment significantly decreased ERα and Bcl-2 protein expression and dramatically increased Bax protein expression compared with the rats in diestrous or proestrous. Rats also underwent 2h of ischaemia via middle cerebral artery occlusion followed by a 24-h reperfusion. Ovariectomy or letrozole treatment significantly decreased the neurological scores and the number of intact neurons detected via Nissl staining and dramatically increased the infarct volume detected via TTC staining and the extent of apoptosis detected via TUNEL staining and Western blotting for cleaved-caspase 3 protein expression. These results demonstrate that endogenous estrogen alleviates ischaemia-reperfusion injury by maintaining Bcl-2 expression via ERα signalling pathway and highlight the neuroprotective effects of endogenous estrogen during different stages of the estrous cycle, providing preliminary information on the underlying mechanism of this process.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zeng-Li
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Department of Anesthesiology, Xi'an Children's Hospital, Xi'an 710032, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Qin
authors.affiliation: Department of Stomatology, Hospital 323 of The People's Liberation Army, Xi'an, Shaanxi 710032, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital to Chinese PLA General Hospital, Beijing 100048, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, General Hospital of Chinese PLA Beijing Command, Beijing 100700, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: You-Liang
authors.initials: YL
authors.lastname: Deng
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.lastname: Yizhao-Liu
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Department of Anesthesiology, Xi'an Traditional Chinese Medicine Hospital, Xi'an 710032, China.
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Xi'an Children's Hospital, Xi'an 710032, China.
authors.forename: Li-Yang
authors.initials: LY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Xi'an Children's Hospital, Xi'an 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: yulongma123@163.com.
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: gangwuhou@163.com.
authors.forename: Wu-Gang
authors.initials: WG
authors.lastname: Hou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D000077289:Letrozole; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009570:Nitriles; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D015398:Signal Transduction; D014230:Triazoles
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D018696:Neuroprotective Agents; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole
keywords: Cerebral ischaemia; Endogenous estrogen; Estrous cycle; Neuroprotection