Esketamine and postoperative cognitive dysfunction in aged mice: Role of the SIRT3/AMPK/mTOR pathway

Background: Postoperative cognitive dysfunction (POCD) frequently occurs after surgery in older patients. Objectives: To investigate whether esketamine (Esk) mitigates POCD in aged mice by regulating the sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. Methods: In this study, a POCD mouse model was established via modified abdominal exploration laparotomy (n=10/group) and an LPS-induced inflammatory model of BV-2 cells was constructed (n=5/group). The effects of Esk on behavior and hippocampal tissue injury in POCD mice were observed through Morris water maze test and pathological staining. The content of inflammatory cytokines, oxidative stress and mitochondrial function-related indicators were detected using kits. Western blot analysis detected SIRT3/AMPK/mTOR pathway and M1 polarization markers levels. Results: POCD mice showed significantly reduced spatial learning and memory abilities, while Esk improved the spatial memory abilities (P<0.05). Esk also alleviated brain tissue damage, neuroinflammation and oxidative stress, inhibited M1 polarization of microglia and improved mitochondrial function in POCD mice. In BV-2 cells, Esk rescued LPS-induced viability reduction, inflammatory factor release and M1 polarization. Mechanistically, Esk regulated SIRT3/AMPK/mTOR pathway, while silencing SIRT3 weakened the neuroprotective effects of Esk. Conclusion: Esk appears to regulate SIRT3/AMPK/mTOR pathway to inhibit neuroinflammation and improve mitochondrial dysfunction, thereby mitigating POCD in aged mice.