Integrative Analysis Revealed Common Genes, Brain Cell-Type and Pathways Between Stiripentol Targets and Risk Genes of Dravet Syndrome and Epilepsy

Abstract Stiripentol is an anti-epileptic drug used for treating Dravet syndrome and epilepsy. To explore common molecular mechanism between antiepileptic effect of stiripentol and genetic etiology of Dravet syndrome and epilepsy, we retrieved target genes of stiripentol through DrugBank database, as well as risk genes of Dravet syndrome and epilepsy from related Database and literature research. Then we performed genetic overlap analysis, Expression Weighted Cell type Enrichment (EWCE) analysis based on single-cell RNA-sequencing (scRNA-seq) data of brain, as well as pathway enrichment analysis. A total of 23, 19 and 118 genes were retrieved for stiripentol targets, risk genes of Dravet syndrome and epilepsy respectively. For stiripentol targets and risk genes of Dravet syndrome, three genes (GABRA1, GABRB3 and GABRG2) were overlapped with P-value of 1.265×10−6; hippocampal CA1 pyramidal cells and interneurons were common brain cell types that were significantly enriched by EWCE; and 10 common pathways were identified. For stiripentol targets and risk genes of epilepsy, five genes (GABRA1, GABRA2, GABRB2, GABRB3, and GABRG2) were overlapped with P-value of 1.963 × 10−7; hippocampal CA1 pyramidal cells and interneurons were also common brain cell types that were significantly enriched and 22 common pathways were identified. Our results revealed that stiripentol might exert its anti-epileptic effect by regulating GABAA receptors on hippocampal CA1 pyramidal cells and interneurons.