Network-based Approach To Predicting The Potential Targets And Drugs For Neuroprotection And Neurorepair In Acute Ischemic Stroke

AIS(Acute Ischemic stroke)is caused by thrombosis and embolism.Hypoperfusion results in restrictiong of brain blood and hypoxic-ischemic of cell,leading to cerebral cell death.Acute ischemic stroke is featured by high incidence,high mortality,high disability and high reoccurrence rates.It also is the most common cause of death and a major cause of disability worldwide.AIS is caused from environment and genetic factors.It is a complicated disease in which many genes involve.In the developmment of AIS,there are many pathophysiology processes,exitotoxicity,oxidative stress,lipid peroxidation and inflammation.Now clinical treatment of AIS is limited to thrombolysis and anticoagulation,with poor effect.Cause death,disability and amount of financial and material resources lossing.In the past studies,many drugs play a good neuroprotective effect in AIS related experiments.But not successfully applied to clinical therapy.So research and development of novel effective neuroprotective and damage repair drugs are imperative.Development of traditional madicine mostly relies on the direct causal relationship between gene products and featured phenotype.Most of these drugs target special targets.New drugs tend to combine with known targets and increase linkages among proteins in network.Recent years,there are two trends in the process of drug development: first,tansfering phenotype-based disease classification system to molecule-based classification system;second,translating the research mode from a single molecule to multiple molecules combined with biological pathways and networks.There is a point of polypharmacology that a drug hits multiple sensitive targets and a target can be impacted by many drugs and provides a new method of drug development for complex diseases.In recent years,the fast development of network medicine provides a network-based model to studying complex diseases.It is helpful in studying global function of disease genes or its products.It is conductive in research of novel disease(especially complex diseases)mechanisms,identification of disease genes and biological pathways and better targets for drug dicovery.Based on network medicine,and combined the using of medicine databases,PPI(proteinprotein interaction),algorithms and related softwares,we globally study interaction among AIS related genes/proteins,to screen out potential targets and candidate drugs of AIS.Firstly,identify AIS related subject headings through searching in Me SH terminology and professors' identification.Based on these terminologies,we found out the disease–gene relationships of AIS.To obtain reliable AIS genes,we manually checked the literatures of the relationships and identified the disease-gene relationships one by one.Taken these reliable genes as seeds and mapped them into PPI network.Caculate the ratios of modules in which disease genes distribute and screen out representative modules.Then depending on information of drugs and targets in databases,study and count distance relation between disease genes and drug targets with statistics and computing network shortest path.Combined with GO and Pathway enrichment analysis,we analyzed the function of modules and screen out important pathway of each module.Followed with the distribution relationship between disease AIS and drug tergets,we extracted nodes which involve in key pathways from modules.Through looking into experiments and literatures,finally identified neuroprotective related potential targets of AIS.Selected out candidate drugs from drug database based on these potential targets.According to the above method,we analyzed 4 modules and identified some potential target from neuroprotective pathways of two modules and found out candidate drugs.In our result,potential target ADORA3(adenosine A3 receptor)involves in the regulation of reprogramming and extracellular matrix.Some candidate drugs are used in the treatment of other neurological diseases.For instance,felbamate and methylphenobarbital used for epilepsy treatment and memantine used for dementia.All of these drugs need further experiments to study their neuroprotective effect in AIS treatment.