Inhibiting endoplasmic reticulum stress alleviates perioperative neurocognitive disorders by reducing neuroinflammation mediated by NLRP3 inflammasome activation

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-10-21 DOI:10.1111/cns.70049

Fanbing Meng, Jian Song, Xinwei Huang, Meixian Zhang, Xiaoxiao Sun, Qi Jing, Silu Cao, Zheng Xie, Qiong Liu, Hui Zhang, Cheng Li

{"title":"Inhibiting endoplasmic reticulum stress alleviates perioperative neurocognitive disorders by reducing neuroinflammation mediated by NLRP3 inflammasome activation","authors":"Fanbing Meng, Jian Song, Xinwei Huang, Meixian Zhang, Xiaoxiao Sun, Qi Jing, Silu Cao, Zheng Xie, Qiong Liu, Hui Zhang, Cheng Li","doi":"10.1111/cns.70049","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aim</h3>\n \n <p>The aim of this study is to explore the key mechanisms of perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Transcriptome sequencing was conducted on hippocampal samples obtained from 18-month-old C57BL/6 mice assigned to control (Ctrl) and A/S groups. The functionality of differentially expressed genes (DEGs) was investigated using Metascape. Hub genes associated with changes between the two groups were screened by combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR and western blotting were used to validate changes in mRNA and protein expression, respectively. NLRP3 inflammasome activation was detected by western blotting and ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress, was administrated preoperatively to explore its effects on the occurrence of PND. Immunofluorescence analysis was performed to evaluate the activation of astrocytes and microglia in the hippocampus, and hippocampus-dependent learning and memory were assessed using behavioral experiments.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>In total, 521 DEGs were detected between the control and A/S groups. These DEGs were significantly enriched in biological processes related to metabolic processes and their regulation. Four hub genes (<i>Hspa5</i>, <i>Igf1r</i>, <i>Sfpq</i>, and <i>Xbp1</i>) were identified. Animal experiments have shown that mice in the A/S group exhibited cognitive impairments accompanied by increased <i>Hspa5</i> and <i>Xbp1</i> expression, ER stress, and activation of NLRP3 inflammasome.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Inhibiting ER stress alleviated cognitive impairment in A/S mice; particularly, ER stress induced by A/S results in NLRP3 inflammasome activation and neuroinflammation. Moreover, the preoperative administration of TUDCA inhibited ER stress, NLRP3 inflammasome activation, and neuroinflammation.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493103/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70049","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Aim

The aim of this study is to explore the key mechanisms of perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes.

Methods

Transcriptome sequencing was conducted on hippocampal samples obtained from 18-month-old C57BL/6 mice assigned to control (Ctrl) and A/S groups. The functionality of differentially expressed genes (DEGs) was investigated using Metascape. Hub genes associated with changes between the two groups were screened by combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR and western blotting were used to validate changes in mRNA and protein expression, respectively. NLRP3 inflammasome activation was detected by western blotting and ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress, was administrated preoperatively to explore its effects on the occurrence of PND. Immunofluorescence analysis was performed to evaluate the activation of astrocytes and microglia in the hippocampus, and hippocampus-dependent learning and memory were assessed using behavioral experiments.

Results

In total, 521 DEGs were detected between the control and A/S groups. These DEGs were significantly enriched in biological processes related to metabolic processes and their regulation. Four hub genes (Hspa5, Igf1r, Sfpq, and Xbp1) were identified. Animal experiments have shown that mice in the A/S group exhibited cognitive impairments accompanied by increased Hspa5 and Xbp1 expression, ER stress, and activation of NLRP3 inflammasome.

Conclusions

Inhibiting ER stress alleviated cognitive impairment in A/S mice; particularly, ER stress induced by A/S results in NLRP3 inflammasome activation and neuroinflammation. Moreover, the preoperative administration of TUDCA inhibited ER stress, NLRP3 inflammasome activation, and neuroinflammation.

Abstract Image

查看原文本刊更多论文

抑制内质网应激可减轻 NLRP3 炎性体活化介导的神经炎症，从而缓解围手术期神经认知障碍。

目的：本研究旨在通过筛选枢纽基因，探索麻醉/手术（A/S）后围手术期神经认知功能障碍（PND）的关键机制：方法：对18个月大的C57BL/6小鼠海马样本进行转录组测序，将其分为对照组（Ctrl）和A/S组。使用 Metascape 研究了差异表达基因（DEGs）的功能。在 CytoHubba 中结合加权基因共表达网络分析筛选出与两组间变化相关的枢纽基因。逆转录 PCR 和 Western 印迹分别用于验证 mRNA 和蛋白质表达的变化。NLRP3 炎症小体的活化通过 Western 印迹和 ELISA 进行检测。术前给予内质网（ER）应激抑制剂牛磺脱氧胆酸（TUDCA），以探讨其对 PND 发生的影响。免疫荧光分析评估了海马中星形胶质细胞和小胶质细胞的激活情况，并通过行为实验评估了海马依赖性学习和记忆：结果：对照组和 A/S 组共检测到 521 个 DEGs。这些 DEGs 在与代谢过程及其调控相关的生物过程中明显富集。发现了四个中心基因（Hspa5、Igf1r、Sfpq 和 Xbp1）。动物实验表明，A/S 组的小鼠表现出认知障碍，同时伴有 Hspa5 和 Xbp1 表达的增加、ER 应激和 NLRP3 炎症体的激活：结论：抑制ER应激可减轻A/S小鼠的认知障碍，尤其是A/S诱导的ER应激会导致NLRP3炎性体活化和神经炎症。此外，术前服用TUDCA可抑制ER应激、NLRP3炎性体活化和神经炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.