Liraglutide alleviates postoperative cognitive impairment via NRF2/NLRP3 signal pathway in aged mice.

Postoperative cognitive dysfunction (POCD) frequently occurs in elderly surgical patients, yet effective preventive strategies are lacking. This study investigated whether the GLP-1R agonist liraglutide (LIR) could alleviate POCD in aged mice and explored the underlying mechanisms. Aged mice underwent laparotomy combined with transient superior mesenteric artery occlusion-a clinically relevant intestinal ischemia-reperfusion model-under sevoflurane anesthesia, followed by 14 days of LIR treatment (300 μg/kg/day). LIR administration improved behavioral performance in the Y-maze and fear conditioning tests. It also decreased microglial activation, promoted an M2-like phenotype, and protected synaptic structures and protein levels. Molecular analysis showed that LIR activated the GLP-1R/NRF2 pathway, reduced reactive oxygen species (ROS) accumulation, and suppressed the expression of NLRP3 inflammasome components. The NRF2 inhibitor ML385 reversed these protective effects. Furthermore, depleting microglia with PLX5622 ameliorated surgery-induced cognitive deficits to near-baseline levels. In these depleted mice, LIR provided no additional cognitive or molecular benefits, suggesting highly overlapping, microglia-dependent mechanisms. These findings indicate that the GLP-1R/NRF2/NLRP3 signaling axis regulates the oxidative stress and inflammatory responses in POCD, highlighting LIR as a potential therapeutic option.