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Epilepsy, ischemic stroke, and depression, as common neurological diseases, pose a serious threat to human health. Although vagus nerve stimulation (VNS) has been applied in the treatment of these diseases, its exact mechanism of action remains unclear. This study aims to deeply analyze the relationships between the core target genes of VNS and epilepsy, ischemic stroke, and depression by integrating network pharmacology, bioinformatics, and Mendelian randomization. The results showed that, compared with the control group, 159 differentially expressed genes were identified in the VNS-treated group. These genes were involved in biological processes such as "protein-RNA complex organization" and are enriched in metabolism-related pathways such as the "AMPK signaling pathway." There were 73, 54, and 108 overlapping genes between VNS-related genes and genes related to epilepsy, ischemic stroke, and depression, respectively. Through network analysis and Mendelian randomization analysis, several core genes that may play a protective role in the corresponding diseases were identified, such as CPT1A, SUCLG1, IMMT, IVD, and PSMA2. This study has revealed the potential molecular mechanisms possibly involved in VNS treatment of these neurological diseases. The findings offer crucial clues for further in-depth study of VNS treatment mechanisms, and may boost the development of more precise and effective treatment strategies.