Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Abstract

Background. Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods. In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results. A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion. Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders

“…Knockdown of MIB2 alleviated the ubiquitination of GPX4 and cognitive injury in aged mice 93 . The inhibitory effects of sevoflurane on SLC7A11 and GPX4 were also observed by our groups in hippocampal neurons 94 . Accordingly, sevoflurane aggravated liver transplantation‐induced brain injury in young rats via its ferroptotic effect 95 .…”

“…93 The inhibitory effects of sevoflurane on SLC7A11 and GPX4 were also observed by our groups in hippocampal neurons. 94 Accordingly, sevoflurane aggravated liver transplantation-induced brain injury in young rats via its ferroptotic effect. 95 Sevoflurane also caused ferroptosis in glioma cells by activating the transcription factor 4 (ATF4)-glutathionespecific gamma-glutamylcyclotransferases 1 (CHAC1) pathway.…”

Treatment with paraquat affects the expression of ferroptosis-related genes

“…These genes have also been associated with ferroptosis in sevoflurane-induced hippocampal neurotoxicity. 42 CHAC1, ATF3, and TFRC promote ferroptosis, whereas SLC7A11 inhibits it. CHAC1, an ER stress response downstream factor, increases cysteine starvation-mediated necrosis and ferroptosis, by stimulating the eIF2-ATF4-DDIT3 pathway for GSH degradation.…”

Role of ferroptosis in effects of anesthetics on multiple organ diseases: A literature review

“…Iron is essential for brain development and multiple neurofunctions [ 30 ]. However, overloaded iron capacity causes neurotoxicity, neurodegenerative diseases, and cognitive impairments via inflammatory response and oxidative stress-induced signaling pathways [ [31] , [32] , [33] , [34] ]. In addition, iron accumulation in the brain can initiate the Fenton reaction and produce ROS, which further induce cell apoptosis and neuro-dysfunction.…”