自噬在吸入麻醉药诱导的老龄大鼠认知功能障碍中的作用及机制

Cognitive impairment is a common postoperative complication in elderly patients, which affects the patients' recovery after surgery. Recently, many studies have suggested that volatile anesthetic was an important factor of the occurrence of cognitive dysfunction in elderly patients or animals. The mechanism has not been fully delineated. Our previous study has showed that the autophagy occurred in the neurons of aged rats after sevoflurane inhalation. Interestingly, autophagy is the pivotal mechanism underlying the degradation of several abnormal proteins aggregation. Thus, autophagy is probably involved in volatile-anesthestics induced postoperative cognitive dysfunction (POCD). This study is to investigate the influence of volatile anesthetics on hippocampal neurons and congnitive function, following autophagy acitivity intervenes by small molecular drugs in volatile anesthestics induced congnitive impaired aged rats. The function of autophagy on inhalation anesthetics induced cognitive dysfunction would be clarified. Furthermore, the differential responses to volatile anesthestics treatment would be evaluated between cultured mature and aging neural cells in vitro. The potential molecular mechanisms underlying the difference would also be analyzed by microarray and protein spectrometry, and the protein targets of volatile anesthestics and relevant regulatory mechanisms could be identified, which would help us to further understand and improve the POCD treatment.

认知功能障碍是老年患者手术后常见的并发症之一，可严重影响患者的康复。目前研究表明，吸入麻醉药是诱发老年患者或老龄动物术后认知功能障碍的重要因素，但其具体机制有待研究。本课题前期研究发现老龄大鼠在吸入七氟烷麻醉后，其神经细胞内出现自噬现象，而自噬是降解异常和损伤蛋白聚集体的关键机制，提示自噬可能在吸入麻醉药诱发认知功能障碍有一定作用。为此本课题拟通过不同小分子药物调控自噬活性来研究吸入麻醉药对老龄大鼠海马神经细胞及认知功能的影响，阐明自噬在吸入麻醉后认知功能障碍中的作用。并进一步应用吸入麻醉药处理体外培养的大鼠神经细胞，观察成熟和衰老神经细胞间反应的差异，利用基因芯片和蛋白质谱技术系统地分析这种差异的潜在分子机制，明确吸入麻醉药作用的关键靶点和相关作用机制，从而针对作用靶点进行自噬能力干预，为临床改善或治疗术后认知功能障碍提供理论依据。

认知功能障碍是老年患者手术后常见的并发症之一，可严重影响患者的康复。目前研究表明，吸入麻醉药是诱发老年患者或老龄动物术后认知功能障碍的重要因素，但其具体机制有待研究。本课题前期研究发现老龄大鼠在吸入七氟烷麻醉后，其神经细胞内出现自噬活动改变，而自噬是降解异常和损伤蛋白聚集体的关键机制，提示自噬可能在吸入麻醉药诱发认知功能障碍有一定作用。为此本项目通过药物干预自噬活性来研究吸入麻醉药对老龄大鼠海马神经细胞及认知功能的影响，结果发现七氟烷在诱导老年大鼠认知功能障碍的同时还会引起海马神经元的自噬障碍，并诱导神经元的凋亡。通过药物干预增强自噬可以缓解自噬障碍，减少神经元凋亡，改善认知功能障碍。而通过药物阻断自噬则效果相反，以上结果提示自噬功能障碍可能是七氟烷引起老龄大鼠认知功能障碍的原因之一。此外，我们研究了七氟烷对H4细胞系自噬及细胞活性的影响，并对其具体机制进行了深入研究，结果发现七氟烷可通过引发内质网应激诱发自噬活动，对细胞活性起保护作用。本项目的研究结果证明了自噬活动在七氟烷引起的认知功能障碍中的作用，为今后预防和干预认知功能功能障碍提供了新的思路和理论基础。