银杏内酯B改善急进高原所致认知功能障碍及对海马神经元钙稳态调控的机制研究

It is still challeging for High Altitude Medicine to maintain high-performance of cognition after rapid ascent to high altitude.In this case ,there is a need to explore the molecular mechanisms underlying cognitive dysfunction induced by acute expose to acute hypobaric hypoxia and to find targeted neuroprotective drugs based on the mechanisms, which might be a new strategy to solve this problem. We have found in our previous studies that Ginkgolide B can significantly ameliorate spatial working memory in rats damaged by expose to acute hypobaric hypoxia and possibly block the L-type calcium channel in neurons. In this study, we design experiments in the whole animal level as well as in cellular and molecular levels to make a detailed investigation. In vivo hippocampus electrophysiology, Whole-cell patch-clamp, the laser copolymerization microscope calcium imaging and molecular biology techniques will be applied to explore the mechanism of Ginkgolide B in alleviating calcium homeostasis in hippocampal neurons of rats induced by rapid high-altitude ascent. With the above study, we are expecting to clarify systematically the mechanism of Ginkgolide B on the protection of cognitive dysfunction induced by rapid high-altitude ascent, and to find out the effective cerebral protective drugs for solving the urgent problem of High Altitude Medicine.

急进高原认知能力的保持是高原医学亟待解决的难题。探索急进高原认知功能障碍的发生机制，并针对相应的机制进行靶向性神经保护药物研究是解决这一难题的新策略。课题组前期研究发现银杏内酯B能够显著改善急进高原大鼠的空间记忆能力以及可能对L型钙通道具有阻断作用，籍此，本项目拟从整体动物、细胞和分子水平，运用在体海马电生理、全细胞膜片钳、激光共聚焦钙成像以及相关分子生物学技术，探讨银杏内酯B对急进高原所致海马神经元胞内钙稳态失调的缓解作用，以期系统阐明银杏内酯B在改善急进高原所致认知障碍中的药效机制，为高原医学亟待解决的难题寻找有效的脑功能保护性药物。

急进高原大脑认知能力的有效保持是高原医学亟待解决的难题。探索急进高原大脑认知功能障碍的发生机制，并针对相应的机制进行靶向性神经保护药物研究是解决这一难题的新策略。本课题组研究发现：银杏内酯B（Ginkgolide B，GB）可有效改善模拟急进6000米高原暴露5天大鼠Morris水迷宫空间记忆能力，其机制可能是①GB可缓解海马神经元氧化应激和细胞凋亡损伤；②GB可抑制神经元突触后兴奋性、动作电位和钙离子电流，降低神经元兴奋性毒性。同时，课题组又发现GB可缓解模拟急进6000米高原6天大鼠的焦虑样行为。综上，本课题研究明确了GB能够改善急进高原大鼠空间记忆能力，初步阐明其作用机制是抗氧化应激、抗细胞凋亡作用，以及调控海马神经元胞内钙稳态平衡作用，初步明确GB可缓解急进高原大鼠焦虑行为。在动物实验水平，GB改善急进高原大鼠大脑空间记忆与抗焦虑作用的明确，为高原医学亟待解决的难题提供了药物防护新靶点与新策略。