Macrophage Migration Inhibitory Factor Inhibitor ISO-1 Attenuates Anesthesia/Surgery-Induced Cognitive Impairment in Aged Mice: Association with NLRP3 Inflammasome Inhibition.

Postoperative cognitive dysfunction (POCD) is a serious clinical complication and lacks effective therapeutic approaches. Recent studies demonstrate that targeting macrophage migration inhibitory factor (MIF) offers a novel strategy to cognitive impairment disorders. Here, we aim to investigate whether MIF inhibitor ISO-1 mitigates anesthesia/surgery-evoked cognitive defects via regulating NLRP3 inflammasome. C57BL/6 mice (18-month-old) were selected to establish a POCD model via unilateral nephrectomy under sevoflurane anesthesia. Cognitive and behavioral capabilities were evaluated by fear conditioning, Morris water maze and open field tests. On day 3 postsurgery, MIF levels in the serum and hippocampus were measured through ELISA, immunofluorescence and western blotting. Furthermore, to clarify whether elevated hippocampal MIF following nephrectomy contribute to cognitive decline, ISO-1 (30 mg/kg) was administered intraperitoneally 30 min before and after surgery to reduce hippocampal MIF expression. ELISA and immunofluorescence were used to gauge the levels of hippocampal MIF, IL-6, TNF-α, IL-1β and microglial activation. HE and TUNEL staining were used to assess the morphological alterations and apoptosis in hippocampal neurons. Western blotting was applied to determine the expression of hippocampal MIF, caspase-1, IL-1β, ASC, NLRP3, Bcl-2, Bax and Iba1. We found that surgery-treated mice exhibited pronounced cognitive impairment, accompanied by increased levels of MIF, neuronal apoptosis and neuroinflammation in the hippocampus, as well as the activation of microglia and NLRP3 inflammasome. Inhibition of MIF with ISO-1 can effectively reverse these detrimental changes. Our results reveal that ISO-1 exerts a neuroprotective effect against POCD, which may be associated with the inhibition of NLRP3 inflammasome activation.