Abstract：Objective: To investigate the effects of remimazolam (RM) on postoperative cognitive dysfunction (POCD) in elderly rats by modulating NLRP3/caspase-1/GSDMD signaling pathway. Methods: A POCD rat model was constructed, and successfully modeled rats were grouped into POCD group, L-RM, M-RM, H-RM groups (intraperitoneal injection of 10, 15, and 20mg/kg RM), and H-RM+NS group (intraperitoneal injection of 20mg/kg RM+gavage of 4mg/kg NLRP3 activator NSS), each with 10 rats. Another 10 normal rats were designated as Control group (only the abdominal cavity was opened without removing the liver lobe). The Control group and POCD group were given equal amounts of physiological saline, once a day for 4 consecutive weeks. Morris water maze experiment was applied to test cognitive function in rats. Nissl staining was used to measure the number of neurons in hippocampus of rats. TUNEL staining was performed to measure neuronal apoptosis in hippocampus of rats. ELISA was used to test inflammatory factors in hippocampal tissue. Western blot was performed to test changes in proteins related NLRP3/caspase-1/GSDMD signaling pathway in hippocampal tissue. Results: The number of hippocampal neurons in the POCD group rats was reduced compared to the Control group, with atrophy and a decrease in Nissl bodies (P<0.05); the L-RM, M-RM, and H-RM groups showed an increase in the number of Nissl bodies and neurons compared to the POCD group, with significant alleviation of atrophy and cell body shrinkage (P<0.05); the H-RM+NSS group exhibited significant neuronal atrophy and fewer Nissl bodies compared to the H-RM group (P<0.05). The POCD group had fewer number of times the platform than the Control group, and higher apoptosis rate of hippocampal neurons, IL-6, TNF-α in hippocampal tissue, NLRP3, caspase-1, and GSDMD-N proteins than the Control group (P<0.05). Compared with the POCD group, the number of platform crossings was higher in rats of the L-RM, M-RM, and H-RM groups, while the hippocampal neuron apoptosis rate, levels of IL-6 and TNF-α in hippocampal tissues, and protein expressions of NLRP3, caspase-1, and GSDMD-N were lower (P<0.05). In contrast, compared with the H-RM group, the H-RM + NSS group showed fewer platform crossings, a higher hippocampal neuron apoptosis rate, elevated levels of IL-6 and TNF-α in hippocampal tissues, and increased protein expressions of NLRP3, caspase-1, and GSDMD-N (P<0.05). Conclusion: RM can improve cognitive function in elderly POCD rats, which may be achieved by inhibiting NLRP3/caspase-1/GSDMD signaling pathway.
2025, Vol. 31 
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