Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β.
Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β.
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雌激素替代疗法诱导的针对脑缺血再灌注损伤的神经保护涉及通过雌激素受体β激活星形胶质细胞
DOI：
10.1038/srep21467
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发表时间：
2016-02-19
影响因子：
4.6
通讯作者：
Hou W
中科院分区：
文献类型：
--
作者：
Ma Y;Guo H;Zhang L;Tao L;Yin A;Liu Z;Li Y;Dong H;Xiong L;Hou W
绝经后妇女缺血性卒中的发病率显著增加。然而，雌激素替代疗法（ERT）对脑卒中的神经保护作用仍存在争议，星形胶质细胞在ERT中的作用很少被探讨。在这项研究中，我们研究了雌激素和选择性雌激素受体（ER）激动剂对星形胶质细胞激活和神经细胞凋亡的影响，在细胞培养的氧和葡萄糖剥夺和再灌注（OGD-R）和全脑缺血（GCI）的条件下。我们证明海马星形胶质细胞主要表达ERβ。在星形胶质细胞中，2.5-20 nM 17β-雌二醇（E2）或10 nM DPN（ERβ激动剂）而非10 nM PPT（ERα激动剂）显著增加GFAP表达。10 nM E2、DPN或E2+MPP（ERα拮抗剂），而不是PPT或E2+PHTPP（ERβ拮抗剂），显著减少星形胶质细胞和神经元共培养物经受OGD-R后的神经元凋亡。我们还发现，无论是50 μg/kg的E2或8 mg/kg的DPN替代（3周）显着增加GFAP的表达和减少GCI诱导的海马CA 1区的神经元凋亡。这些结果表明，雌激素诱导的缺血再灌注损伤的神经保护作用涉及通过ERβ激活星形胶质细胞。因此，星形胶质细胞选择性ERβ调节剂的发现和设计可能为缺血性脑卒中的ERT治疗提供新的策略。
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.