Integrative Network Analysis Reveals Potentially Novel Molecular Mechanisms And Therapeutic Targets Of Intractable Epilepsy

Objective:Epilepsy is a complex brain disorder characterized by recurrent seizures,also severely damages the life and health of humans.Antiepileptic drugs(AEDs)are the main line of treatment for controlling epileptic seizures.However,about a third of the patients do not respond to AEDs,and they are considered to have medically intractable epilepsy.Therefore,the treatment of intractable epilepsy is still one of the challenges.Current research shows that the cause of many epilepsy cases remains unknown,although some people develop epilepsy as a result of gene mutation,stroke,brain injury,brain tumor disorders.The emergence of drug resistance and side effects of traditional first-line drugs encouraged the researchers to search for novel molecular targets and drugs.Network medicine approach has provided the tools to understand the molecular mechanisms and signaling pathways of complex diseases.In this study,we curated comprehensive phenotype-genotype associations related to intractable epilepsy,also worked with multiple databases and network analysis,to investigate the molecular network mechanisms and potential drug targets related to intractable epilepsy,which also provide a new perspective for drug development and disease treatment.Method:1)Using the intractable epilepsy terms from the MeSH terminology,we extracted the seed genes from three databases to construct networks based on the interactions between the proteins they encode;2)utilized the BGL community detection method to divide the human protein-protein interaction(PPI)network to obtain disease-related topological PPI modules;mapped seed genes to module proteins;used Odds Ratio(OR)value to conduct the preliminary screening;3)based on the results of gene ontology(GO)and pathway enrichment analysis of seed genes and preliminary modules,functional similarity analysis between modules,along with the existing AEDs-targets network analysis,to identify disease modules,new potential molecular mechanisms and potential drug targets for intractable epilepsy.Results:1)Based on the 23 MeSH Headings related to intractable epilepsy,1876 disease-gene connections involved with 871 genes of intractable epilepsy were curated by integrating the records from three phenotype-genotype data sources,to build disease-gene network;2)314 topological modules were obtained through dividing PPI network and 921 seed genes distributed in 185 modules;On the basis of the OR value selected 42 modules;3)GO and pathway functional enrichment analysis of seed genes and preliminary modules showed that biological activity of nerve impulses/synaptic transmissions are significant pathological mechanism of epilepsy;voltage-gated potassium channels,neurotransmitter receptor binding and downstream transmission in the postsynaptic cell are most enriched pathways;68 drugs and 119 drug targets,which were used to construct the drug-target network and conduct minimum shortest path analysis,were obtained from Drugbank and Sider databases.Analysis suggested that drug targets mainly enriched in seed genes.Identified three disease modules related to intractable epilepsy(M65,M145 and M155).Combined with the tissue and cell level distribution of the target protein,ten potential drug targets distributed in the three disease modules including KCNA1,KCNA4,KCNA5?KCNA6,KCNC3,KCND2,KCNMA1,CAMK2G,CACNB4 and GRM1 were identified,which provide novel insights into the new drug discovery for intractable epilepsy therapy.Conclusion:In this study,921 seed genes were identified based on the method of network medicine,combined with GO and pathway enrichment analysis which indicated that biological activity of nerve impulses/synaptic transmissions are significant pathological mechanism of epilepsy.On this basis,10 potential drug targets for intractable epilepsy were identified after further study.This study provides a new perspective for the research and understanding the pathogenesis of intractable epilepsy,and also provides a new train of thought for the research and development of potential drug targets and potential new drugs,which is a kind of effective and feasible method for studying complex diseases.