Sevoflurane induces cognitive dysfunction by modulating PER2 methylation to block AKT pathway-suppressed NLRP3 inflammatory vesicle in microglia

作者：Shuangjiang Li, Bin Wang · 发表于：Immunopharmacology and Immunotoxicology · 年份：2025 · DOI：10.1080/08923973.2025.2496666 · 被引用次数：3 · 研究领域：Anesthesia and Neurotoxicity Research、Intensive Care Unit Cognitive Disorders、Eicosanoids and Hypertension Pharmacology

Background The anesthetic sevoflurane can cause cognitive dysfunction and may be involved in mediating DeoxyriboNucleic Acid (DNA) methylation. In this study, we dig into the mechanism of sevoflurane inducing cognitive dysfunction via DNA methylation pathway.Methods In vivo and in vitro experiments were performed in sevoflurane-induced rat models and microglia. In vivo experiments included Morris water maze, Western blot, methylation analysis and immunofluorescence, while in vitro experiments consisted of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. MK2206 was used as a protein kinase B (AKT) inhibitor.Results Sevoflurane induced cognitive dysfunction in rats, promoted levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Interleukin (IL)-18, IL-1β, and ionized calcium-binding adapter molecule 1 (Iba-1) proteins, and inhibited Period2 (PER2) expression by enhancing methylation modification. PER2 was found to be located in microglia. Sevoflurane activated DNA methyltransferases (DNMTs) expression and suppressed PER2 in vitro. PER2 overexpression reduced NLRP3 inflammasomes-related protein expressions and restored AKT activation in sevoflurane-treated cells. Furthermore, MK2206 reversed the inhibitory effect of PER2 overexpression on cellular inflammation and AKT pathway activation.Conclusion Sevoflurane affects AKT pathway-suppressed NLRP3 inflammasomes in microglia by modulating PER2 methylation, thereby contribut...