Differential modulation of estrogen receptors (ERs) in ischemic brain injury:: A role for ER α in estradiol-mediated protection against delayed cell death
Differential modulation of estrogen receptors (ERs) in ischemic brain injury:: A role for ER α in estradiol-mediated protection against delayed cell death
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DOI：
10.1210/en.2005-1177
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Wise, Phyllis M.
中科院分区：
文献类型：
--
作者：
Dubal, Dena B.;Rau, Shane W.;Wise, Phyllis M.
雌二醇可增强受损脑组织的可塑性和存活率。我们以前的工作表明，生理水平的雌二醇通过涉及雌激素受体(ER)和基因表达的变化来保护年轻和老年大脑免受脑缺血的影响。这项研究的主要目的是建立低水平雌激素诱导的神经保护作用的机制。我们首先研究了雌二醇对缺血性脑损伤随时间演变的影响。因为雌二醇会影响细胞的凋亡，我们推测它可以减少大脑中动脉闭塞(MCAO)后细胞死亡的延迟期。此外，由于ER对神经保护至关重要，我们研究了大脑中动脉阻塞后ERα和ERβ两个亚型的时间表达谱，并描绘了每个受体在雌激素介导的神经保护中的潜在作用。用RT-PCR、原位杂交和免疫组织化学方法分析ER的表达。我们发现，在MCAO后的24小时内，雌激素诱导的神经保护机制仅限于减轻延迟性细胞死亡，而不影响即刻细胞死亡。此外，我们发现ER在损伤的演变过程中表现出明显的不同表达谱，ERα的诱导发生在早期，而ERβ的调节发生在较晚的时候。最后，我们为ERα在雌激素介导的脑损伤保护中的新的功能作用提供了证据。这些发现表明，生理水平的雌二醇通过需要ERα的机制来保护中风样损伤后延迟性细胞死亡。
Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ER alpha and ER beta, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ER alpha induction occurring early and ER beta modulation occurring later. Finally, we provide evidence for anew and functional role for ER alpha in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ER alpha.