Exploring the mechanism of tanshinones against intracranial aneurysm rupture using network pharmacology

Abstract

OBJECTIVES: Tanshinones (TSs) have antioxidant and anti-inflammatory functions and have been widely used against several cardiovascular diseases, as well as in treating ruptured intracranial aneurysm (RIA). However, their specific pharmacological mechanism of action remains unknown. This study used network pharmacology to identify the molecular mechanism of action of TSs in the treatment of RIA. METHODS: TSs’ active ingredients and basic information were obtained from the PubChem and Traditional Chinese Medicine Systems Pharmacology (TCMSP) databases. Their predictive targets were obtained from the SwissTargetPrediction, SuperPred, and TCMSP databases. The differentially expressed genes (DEGs) between RIA and ruptured intracranial aneurysm (UIA) were obtained from the Gene Expression Omnibus (GEO) database and analyzed. The intersection between predicted TS and RIA targets was identified. Overlapping target genes were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment to explain potential mechanisms of action. Then, a protein-protein interaction (PPI) analysis was performed and visualized, with the hub genes being screened. Molecular docking was performed using AutoDock Vina and Pymol software. RESULTS: A total of four major active TSs were included for analysis, including tanshinone I (TS-I), tanshinone IIA (TS-IIA), dihydrotanshinone I (DHTI), and cryptotanshinone (CYT). A total of 354 targets were identified as predictive targets of components of TSs. Based on the intersection of the three GSE datasets obtained, a total of 137 common significant DEGs were screened. Additionally, 11 targets common to TSs and RIA were obtained, predicted as TS targets for the treatment of RIA. GO and KEGG pathway enrichment analysis showed that the key target genes had close relationships with nervous system development, chemotaxis regulation, leukocyte chemotaxis, and neurogenesis regulation, which indicated that TSs could decrease inflammatory reactions and improve neural repair. Here, vascular endothelial growth factor A (VEGFA) and growth factor receptor-bound protein 2 (GRB2) were the top potential TS targets for the treatment of RIA. Molecular docking revealed that the essential residues of GRB2 interacted with TS-I and TS-IIA through hydrogen bonds. CONCLUSION: This study identified key targets and potential pathways of TSs in treating RIA, providing a basic guide for their clinical use.