血脑屏障RAGE及LRP1在异氟醚所致β淀粉样蛋白增高中的作用及机制研究

The elevation of amyloid beta-peptide (Aβ) in the brain induced by isoflurane has become a research hotspot in the area of postoperative cognitive dysfunction (POCD) in elderly patients in recent years, among which, the mechanism of Aβ elevation has not been fully elucidated yet. It was demonstrated that the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor related protein 1 (LRP1) at the blood-brain barrier (BBB) were involved in BBB-mediated Aβ transport and clearance, suggesting BBB as a key contributor in isoflurane-induced Aβ elevation in the brain. This study is thus designed to investigate the ultrastructural and functional alterations of BBB, the expression of RAGE, LRP1 and inflammation factors, as well as Aβ deposition in aged rat brain after isoflurane anesthesia. Furthermore, the potential role of BBB integrity in isoflurane anesthesia related neuroinflammation and Aβ deposition in aged rats will be explored by intraperitoneal injection of nuclear factor-κB (NF-κB) inhibitor to specifically inhibit the activation of NF-κB, and hippocampal microinjection of neutralizing anti-RAGE or anti-LRP1 in vivo for intervening Aβ metabolism, respectively. The results of the present study may provide experimental evidence for further exploring the role of alteration of BBB structural and functional integrity in Aβ neurotoxicity after isoflurane anesthesia, and provide a new theoretical basis for elucidating POCD.

吸入麻醉剂异氟醚导致脑内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，其中Aβ增高的机制尚未明确。已报道血脑屏障（BBB）晚期糖基化终产物受体（RAGE）与低密度脂蛋白受体相关蛋白1（LRP1）共同参与并影响Aβ的转运和清除导致POCD，因此推测BBB可能是异氟醚导致Aβ增高的重要环节。本研究拟采用老年大鼠模型，观察异氟醚麻醉对BBB超微结构及功能、RAGE与LRP1表达、神经炎症和脑内Aβ增高的影响；在此基础上，分别采用腹腔注射炎症级联反应枢纽环节核因子-κB的抑制剂和海马微注射抗RAGE、LRP1抗体，干预神经炎症和经BBB途径的Aβ代谢通路，深入探讨异氟醚麻醉后BBB结构及功能完整性的改变对异氟醚所致神经炎症与Aβ增高的影响。研究结果将揭示BBB结构及功能完整性在老年大鼠异氟醚麻醉所致Aβ神经毒性中的可能作用，为阐明POCD发生机制提供实验依据。

吸入麻醉剂异氟醚导致脑内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，其中Aβ增高的机制尚未明确。已报道血脑屏障（BBB）晚期糖基化终产物受体（RAGE）与低密度脂蛋白受体相关蛋白1（LRP1）共同参与并影响Aβ的转运和清除导致POCD，因此推测BBB可能是异氟醚导致Aβ增高的重要环节。本研究拟采用老年大鼠模型，观察异氟醚麻醉对BBB超微结构及功能、RAGE与LRP1表达、神经炎症和脑内Aβ增高的影响；在此基础上，分别采用腹腔注射炎症级联反应枢纽环节核因子-κB的抑制剂和海马微注射抗RAGE、LRP1抗体，干预神经炎症和经BBB途径的Aβ代谢通路，深入探讨异氟醚麻醉后BBB结构及功能完整性的改变对异氟醚所致神经炎症与Aβ增高的影响。结果表明：1.5%异氟醚麻醉4小时可导致老年大鼠BBB occludin蛋白表达下调并导致空间记忆损伤，麻醉后72小时occludin蛋白表达恢复正常；并且1.5%异氟醚麻醉4小时可导致老年大鼠海马HIF-1α表达增高，并且HIF-1α特异性抑制剂YC-1可有效降低HIF-1α、VEGF、MMP-2表达，改善血脑屏障通透性及动物空间学习记忆能力。并且RAGE阻断剂FPS-ZM1可以减轻异氟醚麻醉诱发的老年大鼠术后认知功能障碍，其机制可能与其抑制海马CA1区Aβ沉积有关。以上研究将揭示BBB结构及功能完整性在老年大鼠异氟醚麻醉所致Aβ神经毒性中的可能作用，为阐明POCD发生机制提供实验依据。