Abstract
Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.
Highlights
Xiaoxuming decoction (XXMD) is a well-known traditional Chinese herbal medicine (CHM), which was recorded in BeijiQianjin Yaofang, written by Sun Simiao of the Tang Dynasty, and has been widely used for over centuries in China to treat strokes in clinics [1]
The anti-ischemic activity of XXMD is mediated via numerous mechanisms, including the inhibition of oxidative stress [2], reduction of neuronal apoptosis [3], preservation of mitochondrial integrity and improvement of mitochondrial function [4, 5], reduction in the activity of inducible nitric oxide synthase in cerebral tissues [6], alleviation of blood-brain barrier (BBB) disruption [7], protection of the neurovascular unit [8], suppression of astrocyte activation [9], and regulation of the expression of differentially expressed proteins in the hippocampus [10]
A meta-analysis of eight randomized controlled trials (RCTs) published between 1992 and 2012 revealed that XXMD improves neurological deficits and is safe in patients with acute ischemic stroke when compared to Western conventional medicine (WCM), which was used as the control [1]
Summary
Xiaoxuming decoction (XXMD) is a well-known traditional Chinese herbal medicine (CHM), which was recorded in Beiji. Network-based methods have been used as a novel strategy for discovering the constituents of traditional Chinese medicine (TCM), identifying bioactive compounds, and elucidating the mechanisms underlying the action of herbal formulae [26]. The investigation of TCM using network pharmacology can aid in the discovery of multiple therapeutic targets for the various active ingredients to formulate effective interactions and therapeutic targets This approach can be used to identify the targets, the group of active constituents that play a role in the interactions, and the material basis of the active herbal components of XXMD. We performed molecular docking for investigating the potential synergistic effects of the constituents of different herbs in XXMD on the regulation of vascular tone. The compound-target networks for XXMD were subsequently constructed and analyzed
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