Neuronal mitophagy and mitochondrial health in preventing perioperative neurocognitive disorders in juvenile mice

Abstract Objectives Rapamycin is well-known for its protection in neurodegenerative disorders, and mitochondrial dysfunction-related diseases. However, the mechanisms Rapamycin influences mitophagy in juvenile perioperative neurocognitive disorders (PND), remain poorly understood. Methods Female C57BL/6J mice (4–6 weeks) were randomly allocated to four groups: Control (C), Surgery (S), Surgery+Rapamycin (RAPA, Rapamycin 8 mg kg −1 intraperitoneally (i.p.) every other day for 7 days, 24 h before laparotomy), and Surgery+Rapamycin+3-methyladenine (3-MA+RAPA, 3-MA, 2 mg kg −1 i.p. once daily for 7 days, 1 h before Rapamycin injection). Cognitive performance was assessed on post-operative days 1, 3 and 7; hippocampal ROS, ATP, mitochondrial membrane potential, ultrastructure and mitophagy proteins were subsequently evaluated. Results PND occurred in juvenile mice following laparotomy, as evidenced by a decline in Y-maze alternation rate and novel object recognition, increased ROS levels in the hippocampus, and mitochondrial disruptions. Rapamycin protected PND by enhancing mitophagy in hippocampal neurons, reducing ROS accumulation, and preventing mitochondrial damage. Nevertheless, Rapamycin’s neuroprotective effects were abolished by 3-MA administered. Conclusions Rapamycin protects against juvenile PND by stimulating neuronal mitophagy. It offers new insights for pediatrics, but more clinical trials are needed.