Pharmacological inhibition of Kv1.3 channel reduces sevoflurane-induced cognitive impairment through NLRP3-dependent microglial modulation

Sevoflurane anesthesia is frequently linked to cognitive dysfunction in elderly individuals, with neuroinflammation, particularly microglial activation, playing a critical role in this pathology. Although the potassium channel Kv1.3 has been shown to regulate microglial activation, its involvement in sevoflurane-induced cognitive dysfunction remains poorly understood. In this study, cognitive dysfunction was induced in 17-month-old C57BL/6J mice by exposing them to 3 % sevoflurane for 5 h. Kv1.3 expression and cellular distribution were analyzed using RT-qPCR, Western blot, and immunofluorescence. To investigate the mechanisms underlying this process, mice were pretreated with the selective Kv1.3 inhibitor 5-(4-phenoxybutoxy)psoralen (PAP-1) or the NLRP3 inflammasome inhibitor MCC950 prior to sevoflurane exposure. Behavioral tests, hematoxylin-eosin (H&E) staining, nissl staining, immunohistochemistry, immunofluorescence, Western blot and enzyme-linked immunosorbent assay (ELISA) were performed for further assessment. Sevoflurane exposure led to a significant increase in Kv1.3 expression, which was strongly correlated with cognitive impairments and neuronal damage. Pharmacological inhibition of Kv1.3 with PAP-1 alleviated learning and memory deficits, reduced neuronal damage, and inhibited microglial activation. PAP-1 treatment also promoted the transition of microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype and suppressed NLRP3 inflammasome activation. Furthermore, the NLRP3 inflammasome inhibitor MCC950 also reduced microglial activation and phenotypic shift following sevoflurane exposure. These results suggest that Kv1.3 channel play a critical role in sevoflurane-induced cognitive dysfunction in aged mice through NLRP3-dependent microglial modulation. Targeting Kv1.3 could provide a potential therapeutic strategy for alleviating postoperative cognitive dysfunction associated with sevoflurane anesthesia.