Wang J, Zhang L, Liu B, et al. Systematic investigation of the Erigeron breviscapus mechanism for treating cerebrovascular disease. J Ethnopharmacol. October 5, 2018;224:429–440. doi.org/10.1016/j.jep.2018.05.022.
Cerebrovascular disease (CBVD) refers to diseases involving brain vasculature, such as cerebral atherosclerosis, cerebral ischemia, and cerebral thrombosis. Pharmaceutical treatments for CBVD have numerous unwanted side effects, so alternate therapies are needed. In China, lifeflower (Erigeron breviscapus; Asteraceae) whole herb is used in traditional medicine to treat CBVD. However, the mechanism is not well understood. A new approach to determining the mechanism of action is called systems pharmacology. This technique integrates classical pharmacology, biochemistry, genomics, bioinformatics, computer science, and experimental data from molecules, cells, tissues, and organs. The purpose of this study was to use systems pharmacology to determine the mechanism of action of lifeflower for treating CBVD.
The methodology of this systems pharmacology involves the following steps: (1) molecular database building, (2) oral bioavailability prediction, (3) blood-brain barrier permeation prediction, (4) drug-likeness prediction, (4) molecular targeting, (5) protein-protein interaction (PPI) analysis, (6) gene ontology enrichment analysis, (7) network construction and analysis, (8) pathway contraction and analysis, (9) experimental verification via cell culture, cell viability assay, oxygen-glucose deprivation insult, and drug treatment and Western blot analysis.
Initially 14 potentially active molecules with biological activity were located via the absorption, distribution, metabolism and excretion (ADME) system. Thirteen pharmaceuticals used to treat CBVD were used to identify 34 therapeutic targets. Lifeflower shared two targets with six of the pharmaceuticals. The PPI analysis showed that the two targets were “intimately” connected, and lifeflower could act on CBVD’s therapeutic targets or impact upstream targets, consisting of enzymes, membrane receptors, transcription factors, transporters, and ion channels. The targets play a role in blood pressure regulation, inflammatory response, prostaglandin metabolic process, regulation of smooth muscle contraction, vasoconstriction, oxidative stress, neurotransmitter synthesis, angiogenesis, and vascular endothelial growth factor production. The component-target network was created that showed 511 interactions between 16 molecules from lifeflower and 169 targets. This demonstrates the potential therapeutic effect of lifeflower for CBVDs through modulating multiple targets. To find the essential biological pathways, a target-pathway network was developed with 72 pathways, and three modules emerged; namely, blood pressure regulation, neuroprotection, and angiogenesis. The pathway's key proteins, phosphoinositide 3-kinases (PI3K), phospholipase C gamma (PLCγ), Bax, mitogen-activated protein kinase (MEK), and endothelia nitric oxide synthase (eNOS), were chosen for experimental validation. The cell culture assays revealed that lifeflower promoted angiogenesis and had neuroprotective effects.
The authors conclude that systems pharmacology is an effective technique for understanding the mechanism of action of herbal medicine. The data suggest that lifeflower may be able to treat CBVDs via multiple pathways. The authors declare no conflicts of interest.
—Heather S. Oliff, PhD