Metformin attenuates sevoflurane-induced neurocognitive impairment through AMPK-ULK1-dependent autophagy in aged mice

Abstract

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.

Topics & Concepts