Urolithin A as a Potential Drug for the Treatment of Spinal Cord Injuries: A Mechanistic Study Using Network Pharmacology Approaches.

Abstract

Objective This research was focused to examine the potential targets, action network, and mechanism of urolithin A (UA) in spinal cord injury (SCI) management exploiting the network pharmacology (NP). Methods We used the SwissTargetPrediction, PharmMapper, and TargetNet databases to obtain UA action targets. We searched the OMIM, GeneCards, CTD, and DrugBank databases to screen selected target genes for SCI treatment. The intersection of target genes between the UA and SCI databases was obtained by constructing Venn diagrams, which led to the identification of common druggable targets for the disease. The relationship network of the targets was built with Cytoscape 3.7.2, and the protein interaction network was analyzed with the STRING platform. The protein-protein interaction (PPI) network can be built on the STRING database. Gene Ontology (GO) function and KEGG pathway analyses of target intersections were completed with the DAVID 6.8 database. We constructed preliminary network targets for actions underlying UA-SCI interactions. Using the AutoDock software, we examined the molecular docking interactions between UA and its target proteins and further verified the mechanism of the action of UA. Results We obtained 318 UA drug targets and 1492 SCI disease targets. We identified a total of 118 common UA-SCI targets. Based on the PPI analysis, we identified MAPK1, SRC, AKT1, HRAS, MAPK8, HSP90AA1, MAPK14, JAK2, ESR1, and NF-κB1 as possible therapeutic targets. Enrichment analysis revealed that the PI3K-AKT, VEGF, and TNF signaling pathways could be critical for the NP analysis. Molecular docking indicated that UA had a strong affinity for docked proteins (binding energy range: −6.3 to −9.3 kcal mol−1). Conclusions We employed an NP approach to validate and predict the underlying mechanisms associated with UA therapy for SCI. An additional purpose of this study was to provide a theoretical basis for further experimental studies on UA's potential in SCI treatment.