Background: Sevoflurane, a commonly administered inhaled anesthetic, is found to induce synaptic and mitochondrial damage in neonatal mice. Mitochondrial membrane potential (MMP) changes, mediated by Cyclophilin D (CypD), are implicated in mitochondrial function. Melatonin, known for its significant neuroprotective properties, was investigated in this study to elucidate its mechanisms in mitigating the cognitive impairment caused by sevoflurane.

Methods: The mice were categorized into several groups, including the control, vehicle, sevoflurane, vehicle plus sevoflurane, and melatonin plus sevoflurane groups. From postnatal day 6 to day 8, the mice were administered inhaled sevoflurane or intraperitoneal melatonin. MMP and reactive oxygen species (ROS) were measured using appropriate detection kits. The protein expression levels of PSD95, Synapsin Ⅰ, and CypD in the hippocampus were analyzed through western blotting in acute and prolonged terms. Immunofluorescence staining was used to assess the co-localizations of PSD95 or CypD in parvalbumin (PV) neurons. Cognitive ability was evaluated through novel object recognition, social interaction experiment, and the Morris water maze.

Results: The findings revealed that repeated exposure to sevoflurane in neonatal mice resulted in cognitive and synaptic impairment. Furthermore, melatonin administration suppressed the ROS and CypD protein expression, enhanced the MMP in mitochondria and synaptic protein expression in PV neurons, and ameliorated cognitive deficits.

Conclusion: Melatonin alleviated sevoflurane-induced cognitive deficits by suppressing CypD and promoting synaptic development in hippocampal PV neurons. These results provide valuable insights into a promising therapeutic approach for preventing neurotoxic injuries caused by general anesthetics.

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Xuezhu Zou et al.
Brain Research Bulletin November 2023