Identification of Key Genes in Esketamine's Therapeutic Effects on Perioperative Neurocognitive Disorders via Transcriptome Sequencing.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-02-14 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S510752

Wen Hu, Jieqiong Luo, Hui Li, Yushan Luo, Xiaoyuan Zhang, Zhen Wu, Qian Yang, Sirun Zhao, Bailong Hu, Xiaohua Zou

{"title":"Identification of Key Genes in Esketamine's Therapeutic Effects on Perioperative Neurocognitive Disorders via Transcriptome Sequencing.","authors":"Wen Hu, Jieqiong Luo, Hui Li, Yushan Luo, Xiaoyuan Zhang, Zhen Wu, Qian Yang, Sirun Zhao, Bailong Hu, Xiaohua Zou","doi":"10.2147/DDDT.S510752","DOIUrl":null,"url":null,"abstract":"Background: Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.Methods: The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.Results: The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.Conclusion: We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine's treatment of PND.","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"981-1000"},"PeriodicalIF":5.1000,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836629/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S510752","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.

Methods: The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.

Results: The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.

Conclusion: We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine's treatment of PND.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

通过转录组测序鉴定艾氯胺酮治疗围手术期神经认知障碍的关键基因。

背景：艾氯胺酮可改善异丙酚诱导的小鼠脑损伤和认知功能障碍。然而，艾氯胺酮在围手术期神经认知障碍（PND）中的确切作用和潜在机制尚不清楚。因此，本研究旨在通过动物建模和转录组测序研究艾氯胺酮在PND中作用的相关关键基因。方法：建立PND小鼠模型，给予艾氯胺酮干预，将小鼠分为对照组、手术组和艾氯胺酮手术组。采用Morris水迷宫和Y迷宫范式进行行为评估，并对三组海马样本进行转录组测序。对测序数据进行差异表达分析和加权基因共表达网络分析（WGCNA），确定与艾氯胺酮治疗PND相关的候选基因。随后，利用蛋白-蛋白相互作用（PPI）网络分析筛选出关键基因。对每一步获得的基因进行富集分析，构建关键基因的调控网络。结果Morris水迷宫和Y迷宫的实验结果证实了我们构建的PND模型的成功，表明艾氯胺酮对PND有一定的治疗效果。Ank1、Cbln4、L1cam、Gap43和Shh被指定为后续分析的关键基因。这5个关键基因在胆固醇生物合成、无糖介导的衰变（NMD）、自由40s亚基池的形成、核核和细胞质中rRNA加工的主要途径等方面显著富集。值得注意的是，mmu-mir-155-5p和mmu-mir-1a-3p在功能上共同调节Ank1、Gap43和L1cam的表达。结论：我们揭示了艾氯胺酮治疗PND的疗效，并鉴定了5个关键基因（Ank1、Cbln4、L1cam、Gap43和Shh），为进一步研究艾氯胺酮治疗PND的机制提供了有价值的参考。

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分钟内获得全文去求助

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.