Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance

Summary

Sleep disturbance before surgery worsens postoperative depression and cognitive dysfunction by promoting microglial M1 polarization and disrupting BDNF-TrkB signaling in the brain, leading to emotional changes and cognitive impairments. Treatment with esketamine, the S-enantiomer of ketamine, reversed these behavioral abnormalities by inhibiting microglial M1 polarization and the inflammatory response, thereby improving BDNF-TrkB signaling both in living organisms and in cell cultures. Esketamine also restored impaired hippocampal synaptic plasticity caused by sleep disturbance and surgery. These results suggest that preoperative sleep disruption contributes to postoperative brain complications through inflammatory and neurotrophic mechanisms, and esketamine may offer a protective intervention.

Study at a glance

Abstract

Postoperative depression (POD) and postoperative cognitive dysfunction (POCD) have placed heavy burden on patients’ physical and mental health in recent years. Sleep disturbance before surgery is a common phenomenon that has been increasingly believed to affect patients’ recovery, especially in aged patients, while little attention has been paid to sleep disruption before surgery and the potential mechanism remains ambiguous. Ketamine has been reported to attenuate POCD after cardiac surgery and elicit rapid-acting and sustained antidepressant actions. The present study aimed to clarify the effect of esketamine’s (the S-enantiomer of ketamine) protective effects and possible mechanisms of action in POCD and POD. Our results showed that sleep disturbance before surgery exacerbated microglial M1 polarization and microglial BDNF-TrkB signalling dysfunction induced by surgery, resulting in postoperative emotional changes and cognitive impairments. Notably, treatment with esketamine reversed the behavioural abnormalities through inhibiting the M1 polarization of microglia and the inflammatory response thus improving BDNF-TrkB signalling in vivo and vitro. In addition, esketamine administration also reversed the impaired hippocampal synaptic plasticity which has been perturbed by sleep disturbance and surgery. These findings warrant further investigations into the interplay of esketamine and may provide novel ideas for the implication of preoperative preparations and the prevention of postoperative brain-related complications.