Abstract: Objective To evaluate the effect of dexmedetomidine on sevoflurane-induced cognitive impairment in aged mice and explore the role of the P2X4R/NLRP3 pathway. Methods Sixteen-week-old C57BL/6J mice were randomly divided into four groups (n=16): a control group, a sevoflurane (Sev) group, a dexmedetomidine (Dex) group, and a Dex+Sev group. The Sev group and Dex+Sev group were intraperitoneally injected with dexmedetomidine (20 μg/kg) or normal saline, followed by exposure to 3.2% sevoflurane for 6 h.BV2 Cells were divided into six groups: a control (Con) group, a Con+OE-P2X4R group, a Sev group, a Dex+Sev group, a Dex+Sev+OE-NC group, and a Dex+Sev+OE-P2X4R group. After constructing overexpression models through plasmid transfection, the corresponding cell groups were pretreated with 0.015 mmol/L dexmedetomidine for 24 h, followed by exposure to 4.1% sevoflurane for 6 h.Cognitive function was assessed using the Morris water maze. Immunofluorescence was used to detect microglial activation, neuronal damage, and BV2 cell polarization in the hippocampus of mice. ELISA was used to measure the levels of inflammatory cytokines in the hippocampal tissue and cell culture supernatants. Western blot was used to assess the expression of P2X4R and NLRP3 proteins in hippocampal tissues and BV2 cells. Results Compared with the control group, the Sev group showed a prolonged escape latency, a decreased number of crossings over the original platform, and reduced time spent in the original platform quadrant. Moreover, the Sev group also presented increases in the number of Iba1⁺ cells in the hippocampus and the levels of IL-6, IL-1β, and TNF-α, and decreases in the number of NeuN⁺ cells, with elevated P2X4R and NLRP3 protein expression (P<0.05). Compared with the Sev group, the Dex+Sev group showed a shortened escape latency, an increased number of platform crossings, and extended time spent in the original platform quadrant. Moreover, the Dex+Sev group also presented decreases in the number of Iba1⁺ cells and the levels of IL-6, IL-1β and TNF-α, and increases in the number of NeuN⁺ cells, with reduced P2X4R and NLRP3 protein expression (P<0.05). Compared with the Sev group, BV2 cells in the Dex+Sev group showed weakened relative fluorescence intensity of CD86, reduced levels of IL-6, IL-1β, and TNF-α, enhanced relative fluorescence intensity of CD206, and decreased P2X4R and NLRP3 protein expression (P<0.05). Compared with the Dex+Sev+OE-NC group, BV2 cells in the Dex+Sev+OE-P2X4R group showed enhanced relative fluorescence intensity of CD86, elevated levels of IL-6, IL-1β, and TNF-α in the culture supernatant, weakened relative fluorescence intensity of CD206, and increased P2X4R and NLRP3 protein expression (P<0.05). Conclusions Dexmedetomidine may alleviate sevoflurane-induced neuroinflammation by inhibiting the P2X4R/NLRP3 pathway, thereby preventing cognitive impairment.