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.

中文翻译：

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二甲双胍通过老年小鼠 AMPK-ULK1 依赖性自噬减轻七氟醚诱导的神经认知障碍。

神经认知障碍的风险随着年龄的增长而增加，并在麻醉后进一步增强，导致显着的长期发病率和整体生活质量的降低。二甲双胍激活自噬，这是防止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减轻七氟醚引起的神经认知障碍，并探索了老年小鼠的潜在分子机制。20 个月大的小鼠在有或没有二甲双胍预处理的情况下暴露于 3% 的七氟醚 2 小时。使用莫里斯水迷宫评估认知功能。海马突触完整性通过量化微管相关蛋白 2 (MAP2)、突触后密度蛋白 95 (PSD95) 和突触密度来确定。还测量了海马中的自噬活性和 AMP 活化蛋白激酶 (AMPK) 和 ULK1 磷酸化。二甲双胍预处理减弱了七氟醚引起的空间学习和记忆障碍。同时，七氟醚暴露显着降低了海马突触密度和 MAP2 和 PSD95 免疫反应性，但在二甲双胍预处理组中显示部分恢复。这些二甲双胍介导的神经保护作用被自噬抑制剂 3-甲基腺嘌呤取消。此外，七氟醚麻醉降低了自噬活性，但这种活性被二甲双胍增强，伴随着 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，二甲双胍通过老年小鼠 AMPK-ULK1 依赖性自噬减轻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效药物。