Research Paper Volume 15, Issue 12 pp 5698—5712

Sevoflurane upregulates neuron death process-related Ddit4 expression by NMDAR in the hippocampus

Shuai Li1, , Qi Hou1, , Runjia Wang1, , Yu Hou1, , Qiang Wang1, , Bo Zhang1, , Cheng Ni1, , Hui Zheng1, ,

  • 1 Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Received: February 10, 2023       Accepted: May 26, 2023       Published: June 21, 2023
How to Cite

Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Postoperative cognitive dysfunction (POCD) is a serious and common complication induced by anesthesia and surgery. Neuronal apoptosis induced by general anesthetic neurotoxicity is a high-risk factor. However, a comprehensive analysis of general anesthesia-regulated gene expression patterns and further research on molecular mechanisms are lacking. Here, we performed bioinformatics analysis of gene expression in the hippocampus of aged rats that received sevoflurane anesthesia in GSE139220 from the GEO database, found a total of 226 differentially expressed genes (DEGs) and investigated hub genes according to the number of biological processes in which the genes were enriched and performed screening by 12 algorithms with cytoHubba in Cytoscape. Among the screened hub genes, Agt, Cdkn1a, Ddit4, and Rhob are related to the neuronal death process. We further confirmed that these genes, especially Ddit4, were upregulated in the hippocampus of aged mice that received sevoflurane anesthesia. NMDAR, the core target receptor of sevoflurane, rather than GABAAR, mediates the sevoflurane regulation of DDIT4 expression. Our study screened sevoflurane-regulated DEGs and focused on the neuronal death process to reveal DDIT4 as a potential target mediated by NMDAR, which may provide a new target for the treatment of sevoflurane neurotoxicity.


POCD: Postoperative cognitive dysfunction; DEGs: differentially expressed genes; Cx43: connexin 43; GABAAR: gamma-aminobutyric acid subtype A receptor; NMDAR: N-methyl-D-aspartate receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; qPCR: Real-time qRT-PCR; RAS: renin-angiotensin system.