Xiao Han, Deng Mingyang, Yang Binbin, Tang Jianguang, Hu Zhiping
Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China.
J Neurochem. 2017 Jul;142(2):194-203. doi: 10.1111/jnc.14051. Epub 2017 May 26.
Estrogen receptors have protective effects against ischemic brain injury. However, the molecular mechanisms underlying this phenomenon have yet to be well studied. Given that inhibition of glycogen synthase kinase (GSK3) can reduce cerebral ischemia/reperfusion injury, we hypothesized that estrogen receptors-mediated protective effects against ischemia-induced blood-brain barrier (BBB) disruption involve inhibition of GSK3. Thus, we evaluated GSK3 expression in the brain of ovariectomized female rats, and examined the effects of intracerebroventricular pre-treatments of SB216763, GSK3 inhibitor, on BBB permeability following middle cerebral artery occlusion (MCAO). We also examined the role of specific estrogen receptor subtype in regulation of GSK3 expression and BBB permeability after MCAO. We found that ovariectomized female rats exhibited increased mRNA levels of estrogen receptor α (ERα) and estrogen receptor β (ERβ), and increased protein levels of GSK3β but not GSK3α in brain cortical areas. Furthermore, intracerebroventricular pre-treatments of SB216763 dose-dependently attenuated brain infarction volume, brain water contents, neurological deficits, and BBB disruption, and increased tight junction protein ZO-1 and occludin expression at 24 h following MCAO. Finally, activation of ERβ but not ERα dose-dependently decreased GSK3β expression at 24 h following MCAO. This was associated with increased tight junction protein expression and improved neurological scores. Thus, our study suggested that activation of ERβ may protect against brain ischemia-induced BBB disruption by inhibiting GSK3β-mediated signaling.
雌激素受体对缺血性脑损伤具有保护作用。然而，这一现象背后的分子机制尚未得到充分研究。鉴于抑制糖原合酶激酶（GSK3）可减轻脑缺血/再灌注损伤，我们推测雌激素受体介导的对缺血诱导的血脑屏障（BBB）破坏的保护作用涉及GSK3的抑制。因此，我们评估了去卵巢雌性大鼠脑中GSK3的表达，并研究了脑室注射GSK3抑制剂SB216763预处理对大脑中动脉闭塞（MCAO）后血脑屏障通透性的影响。我们还研究了特定雌激素受体亚型在MCAO后调节GSK3表达和血脑屏障通透性中的作用。我们发现，去卵巢雌性大鼠大脑皮质区域雌激素受体α（ERα）和雌激素受体β（ERβ）的mRNA水平升高，GSK3β的蛋白水平升高，但GSK3α的蛋白水平未升高。此外，脑室注射SB216763预处理在MCAO后24小时剂量依赖性地减轻脑梗死体积、脑含水量、神经功能缺损和血脑屏障破坏，并增加紧密连接蛋白ZO-1和闭合蛋白的表达。最后，在MCAO后24小时，激活ERβ而非ERα剂量依赖性地降低GSK3β的表达。这与紧密连接蛋白表达增加和神经功能评分改善有关。因此，我们的研究表明，激活ERβ可能通过抑制GSK3β介导的信号传导来保护大脑免受缺血诱导的血脑屏障破坏。
