17尾-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion

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• 作者：Jiabin Guo^a ; ^c ; ^d ; Sue P. Duckles^a ; John H. Weiss^b ; Xuejun Li^c ; ^{xjli@bjmu.edu.cn} ; Diana N. Krause^a ; ^{dnkrause@uci.edu}
• 关键词：BSS ; balanced salt solution ; DPN ; 2 ; 3-bis(4-hydroxyphenyl)propionitrile ; E2 ; 17尾-estradiol ; ER ; estrogen receptor ; FCCP ; carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone ; FK ; full kill ; HET ; hydroethidine ; LDH ; lactate dehydrogenase ; MTT ; 3-(4 ; 5-dim
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1-15 June, 2012
• 卷：52
• 期：11-12
• 页码：2151-2160
• 文件大小：1233 K

摘要

17尾-Estradiol (E2) has been shown to protect against ischemic brain injury, yet its targets and the mechanisms are unclear. E2 may exert multiple regulatory actions on astrocytes that may greatly contribute to its ability to protect the brain. Mitochondria are recognized as playing central roles in the development of injury during ischemia. Increasing evidence indicates that mitochondrial mechanisms are critically involved in E2-mediated protection. In this study, the effects of E2 and the role of mitochondria were evaluated in primary cultures of astrocytes subjected to an ischemia-like condition of oxygen-glucose deprivation (OGD)/reperfusion. We showed that E2 treatment significantly protects against OGD/reperfusion-induced cell death as determined by cell viability, apoptosis, and lactate dehydrogenase leakage. The protective effects of E2 on astrocytic survival were blocked by an estrogen receptor (ER) antagonist (ICI-182,780) and were mimicked by an ER agonist selective for ER伪 (PPT), but not by an ER agonist selective for ER尾 (DPN). OGD/reperfusion provoked mitochondrial dysfunction as manifested by an increase in cellular reactive oxygen species production, loss of mitochondrial membrane potential, and depletion of ATP. E2 pretreatment significantly inhibited OGD/reperfusion-induced mitochondrial dysfunction, and this effect was also blocked by ICI-182,780. Therefore, we conclude that E2 provides direct protection to astrocytes from ischemic injury by an ER-dependent mechanism, highlighting an important role for ER伪. Estrogen protects against mitochondrial dysfunction at the early phase of ischemic injury. However, overall implications for protection against brain ischemia and its complex sequelae await further exploration.