异氟醚麻醉后血脑屏障功能/Aβ清除障碍中的自噬作用及其机制研究

The accumulation of amyloid beta-peptide (Aβ) in the brain and blood-brain barrier (BBB) disruption induced by isoflurane have become a research hotspot in the area of postoperative cognitive dysfunction (POCD) in elderly patients in recent years.The existence and functional relevance of autophagy in the brain is increasingly recognized as a major regulator of cognitive function in several neurodegenerative diseases. Nevertheless, the exact role of autophagy in isoflurane-induced neurotoxicity is not clearly understood. Furthermore, our preliminary studies had also revealed that isoflurane exposure triggered a significant inhibition to autophagy activity following a transitory activation in the hippocampus of aged rats, suggesting that autophagy is a key contributor in isoflurane-induced BBB disruption and Aβ elevation. This study is thus designed to investigate the dynamic effect of isoflurane exposure on autophagy activity in aged hippocampus. In addition, the potential role of autophagy in isoflurane anesthesia related BBB disruption and Aβ deposition will be explored by using autophagic inhibitor and inducer to specifically inhibit the activity of mammalian target of rapamycin (mTOR)-dependent and mTOR-independent autophagy. Furthermore, the interplay between isoflurane-induced BBB disruption and Aβ elevation will also be detailly investigated. The results of the present study may provide experimental evidence for further exploring the role of autophagy in isoflurane-induced cognitive dysfunction, and provide a new theoretical basis for elucidating POCD in the elderly patients.

吸入麻醉剂异氟醚导致血脑屏障（BBB）结构及功能失调和脑内β淀粉样蛋白（Aβ）增高是老年患者术后认知功能障碍（POCD）研究的热点。已报道自噬与多种神经退行性疾病相关，但是否参与了异氟醚的神经毒性未见报道。在前期预实验中，我们发现异氟醚麻醉对老龄大鼠海马自噬反应呈短暂激活后转为显著性抑制，故推测异氟醚介导的自噬变化可能参与了麻醉后BBB功能和Aβ代谢紊乱。本研究拟探讨异氟醚对老龄大鼠海马区自噬的动态影响；在此基础上，利用自噬诱导剂和抑制剂干预，研究哺乳动物雷帕霉素靶蛋白（mTOR）依赖和非mTOR依赖的自噬信号通路在这一过程中的调控机制，并进一步探讨BBB结构及功能完整性失调与Aβ清除障碍中的相互作用。研究结果将揭示自噬在异氟醚麻醉后认知功能障碍的可能作用，为阐明老年患者POCD发生机制提供实验依据。

吸入麻醉剂异氟醚导致血脑屏障(BBB)结构及功能失调和脑内β淀粉样蛋白(Aβ)增高 是老年患者术后认知功能障碍(POCD)研究的热点。已报道自噬与多种神经退行性疾病相关， 但是否参与了异氟醚的神经毒性未见报道。在前期预实验中，我们发现异氟醚麻醉对老龄大鼠 海马自噬反应呈短暂激活后转为显著性抑制，故推测异氟醚介导的自噬变化可能参与了麻醉后 BBB功能和Aβ代谢紊乱。本研究拟探讨异氟醚对老龄大鼠海马区自噬的动态影响;在此基础上 ，利用自噬诱导剂和抑制剂干预，研究哺乳动物雷帕霉素靶蛋白(mTOR)依赖和非mTOR依赖的 自噬信号通路在这一过程中的调控机制，并进一步探讨BBB结构及功能完整性失调与Aβ清除障 碍中的相互作用。研究结果将揭示自噬在异氟醚麻醉后认知功能障碍的可能作用，为阐明老年患者POCD发生机制提供实验依据。