Wen Hu,1,* Jieqiong Luo,1,* Hui Li,2,* Yushan Luo,1,* Xiaoyuan Zhang,1 Zhen Wu,1 Qian Yang,1 Sirun Zhao,1 Bailong Hu,2 Xiaohua Zou2 

1Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Bailong Hu; Xiaohua Zou, Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of China, Tel +86-15185184309 ; +86-13809416036, Fax +86-851-86771013, Email 375896605@qq.com; zouxiaohuazxh@163.com

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.

Keywords: esketamine, perioperative neurocognitive disorders, key genes, transcriptome sequencing