Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Neurochem Res. 2020 Feb;45(2):331-344. doi: 10.1007/s11064-019-02918-x. Epub 2019 Dec 21.
Autophagy is crucial for cell survival, development, division, and homeostasis. The mammalian target of rapamycin (mTOR), which is the foremost negative controller of autophagy, plays a key role in many endogenous processes. The present study investigated whether rapamycin can ameliorate surgery-induced cognitive deficits by inhibiting mTOR and activating autophagy in the hippocampus. Both adult and aged C57BL/6J mice received an intraperitoneal injection of rapamycin (10 mg/kg/day) for 5 days per week for one and a half months. Mice were then subjected to partial hepatectomy under general anesthesia. Behavioral performance was assessed on postoperative days 3, 7, and 14. Hippocampal autophagy-related (Atg)-5, phosphorylated mTOR, and phosphorylated p70S6K were examined at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, and tau hyperphosphorylation (T396) in the hippocampus were also examined. Surgical trauma and anesthesia exacerbated spatial learning and memory impairment in aged mice on postoperative days 3 and 7. Following partial hepatectomy, the levels of phosphorylated mTOR, phosphorylated 70S6K, and phosphorylated tau were all increased in the hippocampus. A corresponding decline in BDNF and synaptophysin were observed. Rapamycin treatment restored autophagy function, attenuated phosphorylation of tau protein, and increased BDNF and synaptophysin expression in the hippocampus of surgical mice. Furthermore, surgery and anesthesia induced spatial learning and memory impairments were also reversed by rapamycin treatment. Autophagy impairments and mTOR hyperactivation were detected along with surgery-induced behavioral deficits. Inhibiting the mTOR signaling pathway with rapamycin successfully ameliorated surgery-related cognitive impairments by sustaining autophagic degradation, inhibiting tau hyperphosphorylation, and increasing synaptophysin and BDNF expression.
自噬对于细胞的存活、发育、分裂和内稳态至关重要。雷帕霉素靶蛋白（mTOR）是自噬的主要负调控因子，它在许多内源性过程中发挥着关键作用。本研究探讨了雷帕霉素是否可以通过抑制 mTOR 和激活海马中的自噬来改善手术引起的认知障碍。成年和老年 C57BL/6J 小鼠每周接受 5 天腹腔注射雷帕霉素（10mg/kg/天），持续 1.5 个月。然后，在全身麻醉下对小鼠进行部分肝切除术。在术后第 3、7 和 14 天评估行为表现。在每个时间点检查海马自噬相关（Atg）-5、磷酸化 mTOR 和磷酸化 p70S6K。还检查了海马中的脑源性神经营养因子（BDNF）、突触小体蛋白和 tau 过度磷酸化（T396）。手术创伤和麻醉在术后第 3 和 7 天加重了老年小鼠的空间学习和记忆障碍。部分肝切除术后，海马中磷酸化 mTOR、磷酸化 70S6K 和磷酸化 tau 的水平均升高。BDNF 和突触小体蛋白的表达相应下降。雷帕霉素治疗恢复了自噬功能，减弱了 tau 蛋白的磷酸化，并增加了海马中 BDNF 和突触小体蛋白的表达。此外，雷帕霉素治疗还逆转了手术引起的空间学习和记忆障碍。自噬功能障碍和 mTOR 过度激活与手术引起的行为缺陷同时发生。用雷帕霉素抑制 mTOR 信号通路成功地通过维持自噬降解、抑制 tau 过度磷酸化以及增加突触小体蛋白和 BDNF 的表达来改善与手术相关的认知障碍。
