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

IF 2.9 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2025-05-29 DOI:10.1080/08923973.2025.2496666

Shuangjiang Li, Bin Wang

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引用次数: 0

Abstract

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 contributing to cognitive dysfunction.

查看原文本刊更多论文

七氟醚通过调节PER2甲基化，阻断AKT通路抑制的小胶质细胞NLRP3炎性囊泡，诱导认知功能障碍。

背景：麻醉剂七氟醚可引起认知功能障碍，并可能参与介导脱氧核糖核酸（DNA）甲基化。本研究旨在探讨七氟醚通过DNA甲基化途径诱导认知功能障碍的机制。方法：采用七氟醚诱导大鼠模型和小胶质细胞进行体内、体外实验。体内实验包括Morris水迷宫、Western blot、甲基化分析和免疫荧光，体外实验包括定量实时聚合酶链反应（qRT-PCR）和Western blot。MK2206作为蛋白激酶B （AKT）抑制剂。结果：七氟醚诱导大鼠认知功能障碍，提高核苷酸结合寡聚化结构域样受体蛋白3 （NLRP3）、白细胞介素(IL)-18、IL-1β和离子钙结合接头分子1 （Iba-1）蛋白水平，并通过增强甲基化修饰抑制Period2 （PER2）表达。发现PER2位于小胶质细胞中。七氟醚在体外激活DNA甲基转移酶（dnmt）表达，抑制PER2。在七氟醚处理的细胞中，PER2过表达降低NLRP3炎症小体相关蛋白的表达，恢复AKT的激活。此外，MK2206逆转了PER2过表达对细胞炎症和AKT通路激活的抑制作用。结论：七氟醚通过调节PER2甲基化影响AKT通路抑制的小胶质细胞NLRP3炎症小体，从而导致认知功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).