基于生物信息学方法探究布瓦西坦抗癫痫机制

Bioinformatics-based exploration on antiepileptic mechanism of brivaracetam

目的 探究布瓦西坦抗癫痫关键靶基因,并对其抗癫痫的作用机制进行分析,旨在为癫痫治疗提供理论依据。方法 通过Drugbank数据库获取布瓦西坦靶基因;利用MAGMA软件验证靶基因与GWAS数据遗传信号富集分析;经R语言超几何分布分析布瓦西坦靶基因与癫痫单基因突变相关风险基因的共享基因;从文献检索中获取单细胞测序数据后,利用R语言EWCE包分析布瓦西坦靶基因及单细胞测序数据,获取布瓦西坦靶基因富集神经细胞类型;通过DAVID数据库进行布瓦西坦GO及KEGG富集分析,探究布瓦西坦抗痫的分子机制。结果 通过Drugbank数据库筛选出19个布瓦西坦靶基因。布瓦西坦靶基因与癫痫GWAS数据存在显著相关性,与单基因突变所致癫痫风险基因之间存在显著的遗传共享基因,且主要为电压门控钠离子通道基因。布瓦西坦的靶基因显著富集于中型多棘神经元,其靶基因功能分别富集于电压门控钠通道复合物等细胞组分、钠离子跨膜转运等生物学过程、电压门控钠通道激活等分子学功能,信号转导通路则显著富集于细胞色素P450代谢。结论 布瓦西坦可能通过调节中型多棘神经元中的电压门控钠离子通道相关靶基因发挥其抗痫作用。

Objective:To explore the antiepileptic mechanism of brivaracetam by bioinformatics method.Methods:The target genes of brivaracetam were obtained from Drugbank database;the software of MAGMA were used to verify genetic signal of between targets gene and GWAS data;the shared genes of brivaracetams target gene and risk genes associated with single gene mutation of epilepsy were analyzed by the hypergeometric distribution of R language;R language EWCE package was used to obtain the cell types enriched with the target genes of brivaracetam.The GO and KEGG enrichment analysis of brivaracetam was conducted through DAVID database to explore the antiepileptic molecular mechanisms of brivaracetam.Results:Nineteen target genes of brivaracetam were screened by Drugbank database.The target genes of brivaracetam were significantly associated with epilepsy GWAS data,and showed significant genetic sharing genes with epilepsy risk genes caused by single gene mutations,mainly voltage-gated sodium channel genes.The target genes of brivaracetam were significantly enriched in medium spiny neuron,and they were involved in several cellular components(voltage-gated sodium channel complex),biological processes(sodium ion transmembrane transport)and molecular functions(voltage-gated sodium channel activity).As for signaling pathways,these genes were significantly enriched in the cytochrome P450 metabolism.Conclusion:According to bioinformatics analysis,brivaracetam may exert its antiepileptic effects by regulating the target genes related to voltage-gated sodium channels in medium spiny neuron.