Dexmedetomidine alleviates sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway in aged mice

Abstract

Purpose Microglia-mediated inflammation is associated with perioperative neurocognitive disorders (PNDs) caused by sevoflurane. Dexmedetomidine has been reported to protect against sevoflurane-induced cognitive impairment. In this study, we investigated the effects and underlying mechanisms of dexmedetomidine on sevoflurane-induced microglial neuroinflammation and PNDs. Methods Wild-type and purinergic ionotropic 4 receptor (P2X4R) overexpressing C57/BL6 mice were intraperitoneally injected with 20 μg/kg dexmedetomidine or an equal volume of normal saline 2 h prior to sevoflurane exposure. The Morris water maze (MWM) test was performed to assess cognitive function. Immunofluorescence staining was employed to detect microglial activation. The expression levels of proinflammatory cytokines were measured by real-time quantitative PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The protein levels of P2X4R and NOD-like receptor protein 3 (NLRP3) were detected by Western Blotting. Results Sevoflurane increased the number of microglia, upregulated the levels of proinflammatory cytokines, elevated the protein levels of P2X4R and NLRP3 in the hippocampus and induced cognitive decline, while pretreatment with dexmedetomidine downregulated the protein levels of P2X4R and NLRP3, alleviated sevoflurane-induced microglial neuroinflammation and improved cognitive dysfunction. Moreover, overexpression of P2X4R weakened the neuroprotective effect of dexmedetomidine. Conclusions Dexmedetomidine protected against sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway.