Melatonin Ameliorates Sevoflurane Anesthesia-Induced Deficits in Learning and Memory of Aged Mice Through Nrf2 Signaling Related Ferroptosis

Our research aimed at investigating the protective effects in aged mice exposed to sevoflurane anesthesia. To assess learning and memory abilities and exploratory behavior, the novel object recognition (NOR) test, Morris water maze (MWM) test, and open field test were employed. Commercial kits were used to measure levels of malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide dismutase activity, catalase activity, and iron. The messenger RNA and protein levels of ferritin heavy chain 1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, and glutathione peroxidase 4 in the hippocampus were detected. Treatment with melatonin significantly ameliorated the decrease in exploration time of novel objects and the discrimination index induced by sevoflurane anesthesia. Melatonin also reduced escape latencies and increased the time spent in the target quadrant in the MWM test. In the open field test, melatonin-treated mice exhibited greater exploratory activity, including longer distances traveled and a higher number of rearing events. Further, melatonin treatment markedly decreased the levels of oxidative stress markers and iron in the hippocampus of aged mice exposed to sevoflurane anesthesia. However, the beneficial effects of melatonin were significantly attenuated following treatment with the Nrf2 inhibitor ML385. Our results suggest that melatonin could alleviate learning and memory impairment induced by sevoflurane anesthesia in aged mice through its antioxidant properties, partially through the Nrf2 pathway.