Trimethylamine N-Oxide Mitigates Perioperative Neurocognitive Disorders via ANXA1 Nuclear Translocation and M2 Microglial Polarization in the Hippocampus

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-08-10 DOI:10.1111/cns.70558

Mengxin Que, Li Luo, Xuan Wang, Shiyong Li, Qian Xia, Xing Li, Ailin Luo, Gaofeng Zhan

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Abstract

Aims

This study investigates whether trimethylamine N-oxide (TMAO) mitigates perioperative neurocognitive disorders (PND) by modulating Annexin A1 (ANXA1) and microglial polarization, thereby reducing neuroinflammation in the hippocampus.

Methods

A murine PND model was established via tibial fracture surgery under sevoflurane anesthesia. Mice were pretreated with TMAO (1.2, 12, or 120 mg/kg) for 21 days. Cognitive function was assessed using Y-maze and fear conditioning tests. Hippocampal ANXA1 expression, microglial polarization (M1/M2 phenotypes), and cytokine levels (TNF-α, IL-1β, TGF-β) were analyzed.

Results

TMAO administration (12 mg/kg) significantly improved cognitive performance. Mechanistically, TMAO upregulated ANXA1 expression, facilitating its nuclear translocation in microglia and shifting their polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. This transition consequently suppressed pro-inflammatory cytokines (TNF-α and IL-1β) while elevating TGF-β. Additionally, TMAO attenuated microglial activation and associated neuroinflammatory morphological alterations.

Conclusion

Physiological concentrations of TMAO confer neuroprotection by augmenting ANXA1-mediated resolution of neuroinflammation, supporting its therapeutic potential for preventing PND.

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三甲胺n -氧化物通过海马中ANXA1核易位和M2小胶质极化减轻围手术期神经认知障碍

目的本研究探讨三甲胺n -氧化物（TMAO）是否通过调节膜联蛋白A1 （ANXA1）和小胶质细胞极化，从而减轻海马神经炎症，从而减轻围手术期神经认知障碍（PND）。方法采用七氟醚麻醉下胫骨骨折手术建立小鼠PND模型。小鼠分别用TMAO（1.2、12或120 mg/kg）预处理21天。采用y形迷宫和恐惧条件反射测试评估认知功能。分析海马ANXA1表达、小胶质细胞极化（M1/M2表型）和细胞因子（TNF-α、IL-1β、TGF-β）水平。结果TMAO （12 mg/kg）可显著改善认知能力。从机制上讲，TMAO上调ANXA1的表达，促进其在小胶质细胞中的核易位，并将其极化从促炎M1表型转变为抗炎M2表型。因此，这种转变抑制了促炎细胞因子（TNF-α和IL-1β），同时升高了TGF-β。此外，氧化三甲胺可以减弱小胶质细胞的激活和相关的神经炎症形态学改变。结论生理浓度的氧化三甲胺通过增强anxa1介导的神经炎症消退而具有神经保护作用，支持其预防PND的治疗潜力。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.