Dubal D B, Shughrue P J, Wilson M E, Merchenthaler I, Wise P M
Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
J Neurosci. 1999 Aug 1;19(15):6385-93. doi: 10.1523/JNEUROSCI.19-15-06385.1999.
We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.
我们已经表明，生理水平的雌二醇对大脑中动脉永久性闭塞诱导的缺血性脑皮质具有深远的保护作用。本研究的主要目的是开始阐明雌二醇在损伤中发挥作用的潜在机制。Bcl-2是一种原癌基因，可促进包括大脑在内的多种组织中的细胞存活。由于已知雌二醇在非神经组织中通过Bcl-2促进细胞存活，我们测试了以下假设：雌二醇通过影响缺血性脑损伤中的bcl-2表达来减少细胞死亡。此外，由于雌二醇可能通过雌激素受体介导的机制保护大脑，我们检测了正常和损伤大脑中两种受体亚型ERα和ERβ的表达。我们通过RT-PCR分析了从用雌二醇或油处理的损伤和假手术雌性大鼠获得的大脑皮质微切割区域中的基因表达。我们发现雌二醇可防止损伤诱导的bcl-2表达下调。这种作用对bcl-2具有特异性，因为bcl-2家族其他成员（bax、bcl-x(L)、bcl-x(S)和bad）的表达不受雌二醇处理的影响。我们还发现雌激素受体在损伤中受到不同调节，ERβ的表达与bcl-2的表达平行。最后，我们提供了功能性ERβ蛋白的首个证据，该蛋白能够在大脑缺血中观察到雌二醇介导的神经保护作用的皮质区域内结合配体。这些发现表明雌二醇在缺血性损伤中调节bcl-2的表达。此外，我们的数据表明雌激素受体可能参与激素介导的神经保护作用。
