17β-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion.
17β-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion.
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DOI：
10.1016/j.freeradbiomed.2012.03.005
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发表时间：
2012-06-01
影响因子：
7.4
通讯作者：
Krause, Diana N.
中科院分区：
文献类型：
--
作者：
Guo, Jiabin;Duckles, Sue P.;Weiss, John H.;Li, Xuejun;Krause, Diana N.
17β-雌二醇（E2）已被证明可以预防缺血性脑损伤，但其作用靶点和机制尚不清楚。 E2可能对星形胶质细胞发挥多种调节作用，这可能极大地有助于其保护大脑的能力。线粒体被认为在缺血期间损伤的发展中发挥核心作用。越来越多的证据表明线粒体机制在 E2 介导的保护中发挥着重要作用。在这项研究中，E2 的作用和线粒体的作用在星形胶质细胞的原代培养物中进行了评估，这些星形胶质细胞经历了氧糖剥夺（OGD）/再灌注的缺血样条件。我们发现，E2 治疗可显着防止 OGD/再灌注诱导的细胞死亡（根据细胞活力、细胞凋亡和乳酸脱氢酶渗漏确定）。 E2 对星形胶质细胞存活的保护作用被雌激素受体 (ER) 拮抗剂 (ICI 182,780) 阻断，并被对 ERα 选择性的雌激素受体 (ER) 激动剂 (PPT) 模拟，但不能被对 ERβ 选择性的 ER 激动剂 (DPN) 模拟。 OGD/再灌注引起线粒体功能障碍，表现为细胞活性氧产生增加、线粒体膜电位丧失和 ATP 耗竭。 E2 预处理显着抑制 OGD/再灌注诱导的线粒体功能障碍，并且这种效应也被 ICI 182,780 阻断。因此，我们得出结论，E2 通过 ER 依赖性机制为星形胶质细胞提供直接保护，使其免受缺血性损伤，这凸显了 ERα 的重要作用。雌激素可防止缺血性损伤早期的线粒体功能障碍。然而，对预防脑缺血及其复杂后遗症的总体影响有待进一步探索。
17β-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 to play 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 effect 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 estrogen receptor (ER) agonist selective for ERα (PPT), but not by an ER agonist selective for ERβ (DPN). OGD/reperfusion provoked mitochondria dysfunction as manifested by an increase of 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 concluded that E2 provides direct protection to astrocytes from ischemic injury by an ER-dependent mechanism, highlighting an important role for ERα. Estrogen protects against mitochondria dysfunction at the early phase of ischemic injury. However, overall implications for protection against brain ischemia and its complex sequelae await further exploration.
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DOI：
10.1038/jcbfm.2009.226
发表时间：
2010-03
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Dubal, Dena B.;Rau, Shane W.;Wise, Phyllis M.
通讯作者：
Wise, Phyllis M.
影响因子：
8.8
作者：
Edmands, Scott D.;Hall, Adam C.
通讯作者：
Hall, Adam C.
影响因子：
7.4
作者：
Feng, Z;Zhang, JT
通讯作者：
Zhang, JT
影响因子：
4.8
作者：
Gatson, J. W.;Simpkins, J. W.;Wigginton, J. G.
通讯作者：
Wigginton, J. G.