Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation
Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation
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DOI：
10.1016/j.neuroscience.2007.01.014
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发表时间：
2007-04-25
期刊：
影响因子：
3.3
通讯作者：
Saleh, T. M.
中科院分区：
文献类型：
--
作者：
Connell, B. J.;Crosby, K. M.;Saleh, T. M.
几项研究表明，实验性中风后雌激素介导的神经保护的一种潜在机制是调节谷氨酸介导的兴奋性毒性的结果。我们的实验室已经表明，在雄性大鼠中，雌激素注射（全身性或直接皮质内注射）会导致皮质神经元立即去极化。因此，本研究旨在探讨在介导与这种神经保护相关的早期事件中，雌激素诱导的皮质神经元去极化是否是必需的。我们通过将N - 甲基 - D - 天冬氨酸（NMDA）（MK - 801）或α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）（DNQX）谷氨酸能受体的选择性拮抗剂与雌激素共同注射来验证这一假设。雌激素全身性注射显著减轻了大脑中动脉闭塞（MCAO）后MK801诱导的梗死体积减少。类似地，当雌激素和MK - 801直接共同注射到皮质时，未观察到神经保护作用。然而，当雌激素或MK - 801在另一种药物注射前10分钟集中注射时，观察到了显著的神经保护作用。这使我们假设雌激素介导的神经保护需要NMDA受体的初始激活。此外，我们的结果表明，这种雌激素介导的神经保护还与m - 钙蛋白酶的显著增加以及内质网（ER）特异性半胱天冬酶 - 12的激活有关。最后，电流钳实验结果表明，雌激素显著使皮质神经元去极化，并增强了NMDA诱导的去极化。综上所述，这些结果表明雌激素预处理可能激活NMDA受体，从而导致大脑中动脉闭塞后参与神经保护的内质网相关分子机制发生改变。（c）2007国际脑研究组织。由爱思唯尔有限公司出版。保留所有权利。
Several studies have suggested that a potential mechanism for estrogen-mediated neuroprotection following experimental stroke is a result of modulating glutamate-mediated excitotoxicity. Our laboratory has shown that in male rats, estrogen injection (systemic or direct intracortical injection) resulted in an immediate depolarization of cortical neurons. Therefore, the present study was designed to investigate whether the estrogen-induced depolarization of cortical neurons was required in mediating the early events associated with this neuroprotection. We tested this hypothesis by co-injecting selective antagonists of the NMDA (MK-801) or AMPA (DNQX) glutamatergic receptors with estrogen. Systemic injection of estrogen significantly attenuated the MK801-induced decrease in infarct volume following middle cerebral artery occlusion (MCAO). Similarly, when estrogen and MK-801 were co-injected directly into the cortex, no neuroprotection was observed. However, when estrogen or MK-801 was injected centrally 10 min prior to the injection of the other drug, significant neuroprotection was observed. This led us to hypothesize that estrogen-mediated neuroprotection required an initial activation of NMDA receptors. Furthermore, our results suggest that this estrogen-mediated neuroprotection was also associated with a significant increase in m-calpain and activation of an endoplasmic reticulum (ER) specific caspase-12. Finally, the results of current clamp experiments showed that estrogen significantly depolarized cortical neurons as well as enhanced NMDA-induced depolarization. Taken together, these results suggest that estrogen pretreatment may activate NMDA receptors resulting in modification of ER-associated molecular mechanisms involved in neuroprotection following MCAO. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.