Sigma-1 receptor alleviates postoperative cognitive dysfunction exacerbated by preoperative acute sleep deprivation in mice via modulating the Keap1/Nrf2 signaling pathway

Postoperative cognitive dysfunction (POCD) is a common neurological complication severely affecting patient prognosis. Preoperative acute sleep deprivation, a frequent perioperative stressor, significantly exacerbates POCD severity. Sigma-1 receptor (σ-1R), an endoplasmic reticulum molecular chaperone, plays a crucial role in modulating neuroinflammation and oxidative stress. However, whether σ-1R can serve as an interventional target to mitigate sleep deprivation-aggravated cognitive impairment remains insufficiently elucidated. This study aimed to clarify the regulatory role of σ-1R in a mouse model combining preoperative sleep deprivation with exploratory laparotomy, focusing on Keap1/Nrf2 signaling, and to evaluate its clinical translational potential. Behavioral, molecular biological, and morphological methods were utilized. Sleep deprivation exacerbated postoperative cognitive impairment, accompanied by a compensatory upregulation of σ-1R expression in hippocampal microglia. Notably, exogenous potentiation of σ-1R with the agonist PRE-084 reversed cognitive deficits, suppressed neuroinflammation and oxidative stress, promoted Nrf2 nuclear translocation, and upregulated downstream genes HO-1 and NQO1; conversely, the antagonist BD-1047 worsened the damage. Mechanistically, σ-1R physically associated with Keap1, promoting Nrf2 release. The Nrf2 inhibitor ML385 blocked PRE-084's protective effects. In vitro experiments confirmed PRE-084 alleviated inflammation and oxidative stress via an Nrf2-dependent pathway. Moreover, σ-1R signaling may partially contribute to the neuroprotective effects of dexmedetomidine. In conclusion, this study reveals that σ-1R activation is associated with protective effects in sleep deprivation-exacerbated POCD, potentially through regulating the Keap1/Nrf2 signaling pathway, a mechanism rarely reported in this context, suggesting σ-1R as a potential avenue for further investigation in POCD prevention.