Department of Anaesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China.
Department of Anaesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China.
Brain Res Bull. 2020 Apr;157:18-25. doi: 10.1016/j.brainresbull.2020.01.018. Epub 2020 Jan 31.
Neurocognitive impairment risk increases with age and is further enhanced after anaesthesia, resulting in significant long-term morbidity and an overall reduced quality of life. Metformin activates autophagy, a key process that protects against cognitive dysfunction. We hypothesized that metformin mitigates sevoflurane-induced neurocognitive impairment by regulating autophagy and explored the underlying molecular mechanisms in aged mice. Twenty-month-old mice were exposed to 3 % sevoflurane for 2 h with or without metformin pretreatment. Cognitive function was assessed using the Morris water maze. Hippocampal synaptic integrity was determined by quantifying microtubule-associated protein 2 (MAP2), postsynaptic density protein-95 (PSD95) and synaptic density. Autophagy activity and AMP-activated protein kinase (AMPK) and ULK1 phosphorylation in the hippocampus were also measured. Metformin pretreatment attenuated the sevoflurane-induced spatial learning and memory impairment. Concomitantly, the hippocampal synaptic density and MAP2 and PSD95 immunoreactivity were significantly reduced by sevoflurane exposure but showed partial recovery in the metformin-pretreated group. These metformin-mediated neuroprotective effects were abrogated by 3-methyladenine, an autophagy inhibitor. Furthermore, sevoflurane anaesthesia decreased autophagic activity, but this activity was enhanced by metformin, accompanied by AMPK activation and ULK1 phosphorylation. The AMPK inhibitor compound C abolished metformin-induced ULK1 phosphorylation and autophagy activation after anaesthesia. These results suggest that metformin attenuates sevoflurane-induced neurocognitive impairment through AMPK-ULK1-dependent autophagy in aged mice. Metformin could become a useful drug to ameliorate cognitive impairment in elderly patients after anaesthesia and surgery.
神经认知功能障碍的风险随着年龄的增长而增加，麻醉后进一步增强，导致显著的长期发病率和整体生活质量下降。二甲双胍激活自噬，这是一种保护认知功能障碍的关键过程。我们假设二甲双胍通过调节自噬来减轻七氟醚诱导的神经认知障碍，并在老年小鼠中探讨其潜在的分子机制。将 20 个月大的小鼠暴露于 3%七氟醚中 2 小时，并用或不用二甲双胍预处理。使用 Morris 水迷宫评估认知功能。通过定量微管相关蛋白 2（MAP2）、突触后密度蛋白-95（PSD95）和突触密度来确定海马突触完整性。还测量了自噬活性以及 AMP 激活蛋白激酶（AMPK）和 ULK1 在海马中的磷酸化。二甲双胍预处理可减轻七氟醚引起的空间学习和记忆障碍。同时，七氟醚暴露导致海马突触密度以及 MAP2 和 PSD95 免疫反应性显著降低，但在二甲双胍预处理组中部分恢复。3-甲基腺嘌呤，一种自噬抑制剂，阻断了这些二甲双胍介导的神经保护作用。此外，七氟醚麻醉降低了自噬活性，但二甲双胍增强了自噬活性，同时伴有 AMPK 激活和 ULK1 磷酸化。AMPK 抑制剂化合物 C 消除了麻醉后二甲双胍诱导的 ULK1 磷酸化和自噬激活。这些结果表明，二甲双胍通过 AMPK-ULK1 依赖的自噬减轻老年小鼠七氟醚诱导的神经认知障碍。二甲双胍可能成为改善老年患者麻醉和手术后认知障碍的有用药物。
