Department of Pharmacology, School of Medicine, University of California at Irvine, Irvine, CA 92697, USA.
Free Radic Biol Med. 2012;52(11-12):2151-60. doi: 10.1016/j.freeradbiomed.2012.03.005. Epub 2012 Apr 19.
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 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 ERα (PPT), but not by an ER agonist selective for ERβ (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 ERα. 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.
17β-雌二醇（E2）已被证明可预防缺血性脑损伤，但它的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过程中损伤的发展中起着核心作用。越来越多的证据表明，线粒体机制在 E2 介导的保护中起着至关重要的作用。在这项研究中，评估了 E2 及其在经历类似缺血条件的氧葡萄糖剥夺（OGD）/再灌注的原代星形胶质细胞中的作用。我们发现，E2 处理可显著减轻 OGD/再灌注引起的细胞死亡，如细胞活力、细胞凋亡和乳酸脱氢酶漏出所确定的。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 ERα 选择性激动剂（PPT）模拟，但不受 ERβ 选择性激动剂（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物增加、线粒体膜电位丧失和 ATP 耗竭。E2 预处理可显著抑制 OGD/再灌注诱导的线粒体功能障碍，该作用也被 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了对缺血性损伤的直接保护，突出了 ERα 的重要作用。雌激素在缺血性损伤的早期阶段保护线粒体功能障碍。然而，对于保护大脑免受缺血及其复杂后果的总体影响仍有待进一步探索。
