Liraglutide alleviates postoperative cognitive impairment via NRF2/NLRP3 signal pathway in aged mice
Sun H, Cheng X, Lei D, Liu J, Jin Y, Wang C
Neuroscience Letters (2026)
In aged mice undergoing laparotomy plus transient mesenteric ischemia-reperfusion under sevoflurane, 14 days of liraglutide (300 μg/kg/day) restored Y-maze and fear-conditioning performance, shifted microglia toward an M2 phenotype, preserved synaptic proteins, and activated GLP-1R/NRF2 signalling while suppressing NLRP3 inflammasome — with microglial-depletion experiments showing the mechanism is microglia-dependent.
Sun and colleagues at the Affiliated Yixing Hospital of Jiangsu University investigated whether the GLP-1 receptor agonist liraglutide could alleviate postoperative cognitive dysfunction (POCD) in aged mice. The model combined laparotomy with transient superior mesenteric artery occlusion (a clinically relevant intestinal ischemia-reperfusion intervention) under sevoflurane anesthesia. Aged mice received liraglutide 300 μg/kg/day for 14 days post-procedure.
Behavioral testing showed liraglutide improved performance on the Y-maze (spatial working memory) and the fear-conditioning test (associative memory). Cellular analysis demonstrated reduced microglial activation and a shift toward an M2-like anti-inflammatory phenotype, with preservation of synaptic structures and protein levels. Molecular pathway analysis showed liraglutide activated the GLP-1R/NRF2 axis, reduced reactive oxygen species accumulation, and suppressed NLRP3 inflammasome component expression. Pharmacological NRF2 inhibition with ML385 abrogated the protective effects, confirming pathway dependence. In a microglia-depletion arm using PLX5622, surgery-induced cognitive deficits were ameliorated to near-baseline levels; in microglia-depleted mice, liraglutide provided no additional cognitive or molecular benefit, indicating the mechanism is microglia-mediated and not a parallel non-microglial pathway.
This is a preclinical aged-mouse study with a focused mechanistic readout; clinical POCD trials with GLP-1 receptor agonists have not yet been published, so the translational claim is hypothesis-generating. The dose of 300 μg/kg/day is supra-clinical relative to human dosing per kg of body weight; mouse-to-human dose scaling for liraglutide is non-trivial because of differences in plasma protein binding and clearance.
The intestinal ischemia-reperfusion model is one of several aged-mouse POCD models; it is most relevant to abdominal surgery with vascular involvement and may not generalise to elective orthopedic or cardiac surgery POCD phenotypes. Behavioral test selection captures specific memory domains; broader cognitive batteries are not reported in the abstract. Sample sizes per arm and statistical methods are not in the abstract. Abstract-only extraction.
There are no human data on liraglutide and POCD; the closest comparator literature is the EVOKE / GLP-1 RAs-in-Alzheimer's trial set, where the clinical-cognitive signal has been mixed.
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