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Abstract
Guanxin-Shutong capsule (GXSTC), a combination of Mongolian medicines and traditional herbs, has been clinically proven to be effective in treating cerebrovascular diseases (CBVDs). However, the underlying pharmacological mechanisms of GXSTC in CBVDs remain largely unknown. In this study, a combination of systems pharmacology and experimental assessment approach was used to investigate the bioactive components, core targets, and possible mechanisms of GXSTC in the treatment of CBVDs. A total of 15 main components within GXSTC were identified using high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) and a literature research. Fifty-five common genes were obtained by matching 252 potential genes of GXSTC with 462 CBVD-related genes. Seven core components in GXSTC and 12 core genes of GXSTC on CBVDs were further determined using the protein-protein interaction (PPI) and component-target-pathway (C-T-P) network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results predicted that the molecular mechanisms of GXSTC on CBVDs were mainly associated with the regulation of the vascular endothelial function, inflammatory response, and neuronal apoptosis. Molecular docking results suggested that almost all of core component-targets have an excellent binding activity (affinity < −5 kcal/mol). More importantly, in middle cerebral artery occlusion (MCAO) -injured rats, GXSTC significantly improved the neurological function, reduced the infarct volume, and decreased the percentage of impaired neurons in a dose-dependent manner. Western blotting results indicated that GXSTC markedly upregulated the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS), while downregulating the expression of cyclooxygenase-2 (COX-2) and transcription factor AP-1 (c-Jun) in MCAO-injured rats. These findings confirmed our prediction that GXSTC exerts a multi-target synergetic mechanism in CBVDs by maintaining vascular endothelial function, inhibiting neuronal apoptosis and inflammatory processes. The results of this study may provide a theoretical basis for GXSTC research and the clinical application of GXSTC in CBVDs.
Highlights
Cerebrovascular diseases, characterized by stroke and other forms of neurological dysfunction and degeneration, are among the most common causes of morbidity and mortality worldwide, seriously affecting human health and life (Collaborators., G.B.D.N., 2019)
Based on the TCMSP databases and on literature research, five components were primarily derived from Choerospondiatis fructus, eight components were primarily produced by Radix Salviae miltiorrhizae, and two components were derived from Salviae miltiorrhizae
The results indicated that these core component-targets had a strong binding activity, and further confirmed the reliability of the interactions predicted by using systemic pharmacology
Summary
Cerebrovascular diseases, characterized by stroke and other forms of neurological dysfunction and degeneration, are among the most common causes of morbidity and mortality worldwide, seriously affecting human health and life (Collaborators., G.B.D.N., 2019). There is a pressing need to develop safer and more effective drugs for CBVDs. Traditional Chinese medicine (TCM) has been used for thousands of years to prevent and treat CBVDs. GuanxinShutong capsule, a combination of Mongolian medicines and traditional herbs, has been commonly used to treat angina pectoris and coronary heart diseases in China (Li et al, 2019); it consists of Choerospondias axillaris (Roxb.) B.L.Burtt and A.W.Hill [Anacardiaceae; Choerospondiatis fructus], Salvia miltiorrhiza Bunge [Lamiaceae; Radix Salviae miltiorrhizae], Syzigium aromaticum (L.) Merr. Several clinical trials have further demonstrated that GXSTC has a significant clinical effect in treating ischemic stroke, and could markedly improve the nerve function of stroke patients (Wu, 2015; Shao, 2018). The effective components and potential mechanisms of action of GXSTC against CBVDs remain unclear
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