Anti-inflammatory effects of vagus nerve stimulation in pediatric patients with epilepsy

Abstract

Introduction: The neural control of the immune system by the nervous system is critical to maintaining immune homeostasis, whose disruption may be an underlying cause of several diseases, including cancer, multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease.

Methods: Here we studied the role of vagus nerve stimulation (VNS) on gene expression in peripheral blood mononuclear cells (PBMCs). Vagus nerve stimulation is widely used as an alternative treatment for drug-resistant epilepsy. Thus, we studied the impact that VNS treatment has on PBMCs isolated from a cohort of existing patients with medically refractory epilepsy. A comparison of genome-wide changes in gene expression was made between the epilepsy patients treated and non-treated with vagus nerve stimulation.

Results: The analysis showed downregulation of genes related to stress, inflammatory response, and immunity, suggesting an anti-inflammatory effect of VNS in epilepsy patients. VNS also resulted in the downregulation of the insulin catabolic process, which may reduce circulating blood glucose.

Discussion: These results provide a potential molecular explanation for the beneficial role of the ketogenic diet, which also controls blood glucose, in treating refractory epilepsy. The findings indicate that direct VNS might be a useful therapeutic alternative to treat chronic inflammatory conditions.

Keywords: blood glucose; cytokines; insulin; neuroimmune; peripheral blood monocytes cells; seizure; tumor necrosis factor; vagus nerve stimulation.

Figure 1

Transcriptome profiling of upregulated genes in patients treated with vagus nerve stimulation. Gene ontology (GO) enrichment analysis of upregulated genes in the patients treated with VNS vs. non- treated with P value of less than 0.05 and fold change more than 2 are included in the figure. The bars represent the different GO categories ordered by enrichment fold change shown on the x axis.

Figure 2

Transcriptome profiling of down-regulated genes in patients treated with vagus nerve stimulation. Gene ontology (GO) enrichment analysis of downregulated genes with P value of less than 0.05 and fold change of less than 0.5 are included in the figure. The bars represent the different GO categories ordered by enrichment fold change shown on the x axis. The category with the highest fold enrichment is at the bottom of the graph, while the lowest one is at the top of the graph.

Figure 3

Functional annotation analysis of downregulated genes into three main categories using DAVID. (A) Representative bar graphs showing the significantly enriched genes associated with the biological process. The vertical lines represent the different biological processes involved and the horizontal and the length represent the fold enrichment. (B) Representative bar graphs showing the significantly enriched genes associated with the activities at the molecular level. The y-axis represents the different molecular functions ordered with the fold enrichment on the x-axis. (C) Representative bar graphs showing the significantly enriched genes associated with the cellular structures in which a gene functions and is termed as the cellular component. The y-axis represents the different cellular components ordered with the fold enrichment on the x-axis.

Figure 4

KEGG pathway classification of the upregulated genes. Pie charts showing the distribution of the KEGG pathways for the upregulated genes. The pathways were obtained by using DAVID. Different colors represent different pathways, and the percentage numbers represent the fold enrichment of the genes associated with that pathway.

Figure 5

KEGG pathway classification of the downregulated genes. Pie charts depict the distribution of the KEGG pathways for the downregulated genes. The pathways were obtained by using DAVID. Different colors represent different pathways, and the percentage numbers represent the fold enrichment of the genes associated with that pathway.