Yan Wen-Jun, Wang Da-Bin, Ren Dong-Qing, Wang Ling-Kai, Hu Zhong-Yuan, Ma Ya-Bing, Huang Jin-Wen, Ding Shao-Li
Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China.
J Cell Biochem. 2019 Jul;120(7):11633-11641. doi: 10.1002/jcb.28443. Epub 2019 Feb 18.
Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients who undergo surgery involving anesthesia. Its underlying mechanisms remain unclear. Autophagy plays an important role in the damage and repair of the nervous system and is associated with the development of POCD. Using a rat model, adenosine monophosphate-activated protein kinase α1 (AMPKα1), an important autophagy regulator, was found to be significantly downregulated in rats with POCD that was induced by sevoflurane anesthesia or by appendectomy. Overexpression of AMPKα1-ameliorated POCD, as indicated by decreased escape latencies and increased target quadrant swimming times, swimming distances, and platform crossing times during Morris water maze tests. AMPKα1 overexpression activated autophagy signals by increasing the expression of light chain 3 II (LC3-II) and Beclin1 and decreasing the expression of p62 in the hippocampus of rats with POCD. Moreover, blocking autophagy by 3-methyladenine partly attenuated AMPKα1-mediated POCD improvement. Furthermore, overexpression of AMPKα1 could upregulate the expression of p-AMPK and Sirt1 in the hippocampus of rats with POCD. Intriguingly, inhibiting AMPK signals via Compound C effectively attenuated AMPKα1-mediated POCD improvement, concomitant with the downregulation of p-AMPK, Sirt1, LC3-II, and Beclin1 and the upregulation of p62. We thus concluded that overexpression of AMPKα1 can improve POCD via the AMPK-Sirt1 and autophagy signaling pathway.
术后认知功能障碍（POCD）是接受涉及麻醉的手术的老年患者中常见的并发症。其潜在机制尚不清楚。自噬在神经系统的损伤和修复中起重要作用，并且与POCD的发生有关。使用大鼠模型，发现单磷酸腺苷激活的蛋白激酶α1（AMPKα1），一种重要的自噬调节因子，在由七氟醚麻醉或阑尾切除术诱导的POCD大鼠中显著下调。AMPKα1的过表达改善了POCD，如在莫里斯水迷宫试验中逃避潜伏期缩短以及目标象限游泳时间、游泳距离和平台穿越次数增加所表明的。AMPKα1过表达通过增加POCD大鼠海马中轻链3 II（LC3-II）和Beclin1的表达并降低p62的表达来激活自噬信号。此外，用3-甲基腺嘌呤阻断自噬部分减弱了AMPKα1介导的POCD改善。此外，AMPKα1的过表达可以上调POCD大鼠海马中p-AMPK和Sirt1的表达。有趣的是，通过化合物C抑制AMPK信号有效地减弱了AMPKα1介导的POCD改善，同时伴随着p-AMPK、Sirt1、LC3-II和Beclin1的下调以及p62的上调。因此，我们得出结论，AMPKα1的过表达可以通过AMPK-Sirt1和自噬信号通路改善POCD。
