Study on the effect and mechanism of Win55, 212-2 on GP120-induced HAND in rats based on network pharmacology

Objective:To explore the effect and mechanism of Win55, 212-2 on human immunodeficiency virus type 1 (HIV-1) envelope protein GP120-induced HIV-1-associated neurocognitive disorders (HAND) in rats based on network pharmacology.Methods:First, HAND related targets were obtained from GeneCards, OMIM, DisGeNET and NDCI databases, and Win55, 212-2 related targets were obtained from GeneCards, Pharm Mapper and SwissTargetPrediction.Then, the intersection targets of HAND and Win55, 212-2 were obtained by using Venny 2.1.0 online tool.The protein interaction (PPI) network of intersection targets was constructed by String 11.5 database and Cytoscape 3.7.2 software, and the core targets were screened out.GO and KEGG pathway enrichment analysis was performed for intersection targets using David 6.8 database, and the enrichment results were visualized using bioinformatics softwares.Finally, a network model diagram of "drug-target-disease-pathway" was constructed by using Cytascape 3.7.2 software.The rat model of GP120-induced HAND was established by stereotactic injection into the brain, and the new object recognition test (NORT) was performed on the third day after surgery to detect the cognitive function of each group of rats.Real-time fluorescence quantitative polymerase chain reaction (RTqPCR) was used to detect the mRNA expression levels of P38 MAPK pathway and downstream inflammatory factors TNF-a and CXCL-12 in the hippocampus of rats in each group.Results:There were 81 common targets of Win55, 212-2-HAND, and the results of GO and KEGG analysis showed that the core targets of Win55, 212-2 for HAND treatment included AKT1, TNF, ALB and MAPK3, etc.The main pathways involved cAMP signaling pathway, AGE-RAGE signaling pathway, TNF signaling pathway and MAPK signaling pathway, etc.The new object recognition test (NORT) results showed that Win55, 212-2 increased the discrimination index of GP120-induced HAND rats, and RT-qPCR results showed that Win55, 212-2 decreased the mRNA expression levels of P38, TNF-α and CXCL-12(all P< 0.01).Conclusion:Win55, 212-2 plays a neuroprotective role by down-regulating P38 MAPK pathway and inhibiting the expression of downstream inflammatory factors TNF-α and CXCL-12, which may be the mechanism of improving GP120-induced HAND in rats.