Investigation of the Multi-Target Mechanism of Guanxin-Shutong Capsule in Cerebrovascular Diseases: A Systems Pharmacology and Experimental Assessment

Juanli Zhang; Jiaxin Zhao; Yang Ma; Wenjun Wang; Shaojie Huang; Chao Guo; Kai Wang; Xiaomei Zhang; Wei Zhang; Aidong Wen; Ming Shi; Yi Ding

doi:10.3389/fphar.2021.650770

Investigation of the Multi-Target Mechanism of Guanxin-Shutong Capsule in Cerebrovascular Diseases: A Systems Pharmacology and Experimental Assessment

Front Pharmacol. 2021 May 13:12:650770. doi: 10.3389/fphar.2021.650770. eCollection 2021.

Authors

Juanli Zhang^{1

2}, Jiaxin Zhao¹, Yang Ma¹, Wenjun Wang¹, Shaojie Huang¹, Chao Guo¹, Kai Wang¹, Xiaomei Zhang³, Wei Zhang¹, Aidong Wen¹, Ming Shi², Yi Ding¹

Affiliations

¹ Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
² Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
³ Basic Medical School, Yunnan University of Traditional Chinese Medicine, Kunming, China.

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.

Keywords: cerebrovascular diseases; experimental assessment; guanxin-shutong capsule; multi-target mechanism; systems pharmacology.