Abstract

BACKGROUND The NOD-like receptor protein 3 (NLRP3) inflammasome serves as a critical hub connecting intestinal ischemia-reperfusion (IIR) injury and post-operative cognitive dysfunction (POCD). Thiolutin (THL) is a potent anti-inflammatory agent with demonstrated potential to modulate NLRP3 inflammasome activation, its therapeutic potential for IIR-induced POCD in aged mice is still unclear. METHODS Young adult and aged mice were subjected to IIR. Cognitive function was assessed using the Morris Water Maze and Novel Object Recognition (NOR) tests. Intestinal permeability was evaluated through serum FITC-dextran and lipopolysaccharide (LPS) measurements, while bacterial translocation was quantified via portal vein blood culture. Histopathological analysis, TUNEL staining, and Western blot were performed to assess intestinal injury and pyroptosis. Neuroinflammation was evaluated by measuring pro-inflammatory cytokines and microglial activation. RESULTS IIR induced significant cognitive impairment in aged mice compared to young adults. THL treatment markedly ameliorated intestinal injury, reduced intestinal permeability (FITC-dextran and LPS levels), and decreased bacterial translocation. Furthermore, THL significantly attenuated IIR-induced cognitive deficits, restored the expression of synaptic proteins (BDNF, synaptophysin, and PSD-95), and inhibited microglial activation. Mechanistically, THL suppressed IIR-induced pyroptosis, and this effect was accompanied by downregulation of the BRCC3/NLRP3 pathway in both intestinal and cerebral tissues, suggesting a potential link. CONCLUSION THL protects against IIR-induced POCD in aged mice by improving intestinal barrier function and inhibiting cerebral neuroinflammation, potentially via the BRCC3/NLRP3 axis, highlighting THL as a potential therapeutic agent for preventing POCD in elderly surgical patients.