Exploration of Key Genes and Molecular Mechanisms in Mice with Perioperative Neurocognitive Disorders Treated with Remimazolam Based on Transcriptomics and Experimental Verification.

BACKGROUND

As the number of elderly patients grew, perioperative neurocognitive disorder (PND) from drug - induced anesthesia and surgery drew more attention. Studies showed remimazolam could reduce PND. Thus, exploring key target genes in remimazolam's intervention of PND was crucial.

METHODS

In this study, behavioral observations were conducted using the PND model. Hippocampal tissues from 15 mice (5 PND, 5 PND, and 5 intervention groups) were collected for total RNA extraction and mRNA sequencing. Candidate genes were identified via differential expression analysis and intersection. Key genes were determined through overlapping three algorithms in protein-protein interaction (PPI) analysis and expression verification. Functional enrichment, immune infiltration, and molecular docking analyses were performed, with their expression levels further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

RESULTS

There were significant differences in the behavior of mice among different groups. Based on the intersection of up-and down-regulated genes in 357 differentially expressed genes1 (DEGs1) and 323 DEGs2, a total of 38 candidate genes were identified. Finally, we selected and as the key genes for subsequent study. Moreover, the PCR results showed that the expression of key genes in the PNG group was nearly twice that of the control group (p < 0.05). In-depth research revealed that pathways like glutamate receptor binding, tau protein binding, and GABA-gated chloride ion channel activity played important roles in disease occurrence. Meanwhile, 5 immune cells (including dendritic cells, macrophages, and gamma delta T cells) showed substantial differences between the model and PND groups, potentially contributing to disease development. Additionally, only Jph3 was regulated by mmu-miR-6969-5p and mmu-miR-186-5p. Both Jph3 and Caly had good binding abilities with remimazolam (< -5.0 kcal/mol), highlighting their potential as therapeutic agents for PND.

CONCLUSION

This study identified 2 validated key genes (Jph3 and Caly), providing potential therapeutic targets for PND patients.