Clinical Applications and Mechanisms of Action of Huangqi Guizhi Wuwu Tang for Stroke–Related Muscular Numbness and Weakness: Literature Reviews and Computational Analyses
Creators: name: Lee, Sanghyun
Publisher: name: RMIT University
Year: 2025
Subjects: classificationCode: 420803
subject: Traditional Chinese medicine and treatments

description: Stroke–related numbness and weakness (SRNW) is a common symptom in post–stroke patients. Although SRNW is not a life–threatening condition, over 85% of post–stroke patients experience it. Current management for SRNW includes drug and non–drug interventions, such as pharmaceutical treatments, rehabilitation programs, and alternative therapies. However, these treatments do not fully address SRNW, and some may have adverse consequences. Therefore, some post–stroke patients eventually consider seeking alternative options for managing SRNW. Chinese herbal medicine has historically been used for post–stroke management. Huangqi Guizhi Wuwu Tang (HGWT) is one of the herbal formulas that has been widely used for managing SRNW for over 1800 years. However, its mechanisms of action for managing SRNW are not clearly understood. The current research project aimed to review the classical literature, conduct a systematic review of randomised controlled trials (RCTs), evaluate experimental studies, and perform computational analyses to assess the effects and safety of HGWT. 

Phase I: A classical literature review of Huangqi Guizhi Wuwu Tang 
A total of 33 texts in 31 classical books were identified in the comprehensive review of classical literature by searching the compact disc, Encyclopedia of Traditional Chinese Medicine (Zhong Hua Yi Dian). This review indicates that HGWT has been used for managing stroke–like signs and symptoms in traditional Chinese medicine. Even though the term “stroke” did not exist in ancient times, stroke–like symptoms were described using terms such as Xue Bi (血痹) and Shen Ti Bu Ren (身体不仁). The Phase I study highlights the primary findings regarding HGWT and its variations used to treat Xue Bi (血痹) and Shen Ti Bu Ren (身体不仁), as mentioned in 24 of the 33 texts. These conditions are recognised as post–stroke symptoms in modern Chinese medicine clinical practice. The original HGWT includes five herbs: Astragali Radix (Huang qi), Paeoniae Radix Alba (Bai shao), Cinnamomum Ramulus (Gui zhi), Jujubae Fructus (Da zao), and Zingiberis Rhizoma Recens (Sheng jiang). 

Phases II and III: Reviews of modern clinical and experimental studies 
The systematic review of clinical studies, following the methods described in the Cochrane Handbook for Systematic Reviews of Interventions, indicated that 25 RCTs used HGWT or modified HGWT combined with other interventions and measured a variety of outcome measures. These 25 RCTs were grouped into three categories: shoulder–hand syndrome, hemiplegia, and other symptoms which could not be categorised in the other two. The top three outcome measures were clinical effectiveness rate (n=17), Fugl–Meyer assessment (n=11), and visual analogue scale (n=9). The meta–analyses showed that HGWT or modified HGWT combined with other interventions improved those outcome measures. There was encouraging evidence of HGWT’s beneficial effects as an add–on therapy to other interventions to improve post–stroke management. The five herbs contained in the original HGWT have been frequently used in modern clinical studies. 

The experimental studies evaluated HGWT’s therapeutic effects and safety for SRNW through pharmacokinetics and pharmacodynamics, toxicity and phytochemistry profiles. Fourteen studies were included in the review of experimental in vitro and in vivo studies. In a pharmacodynamic study, a cerebral artery thrombosis model in a rat group showed significantly decreased cerebral infarction and vascular injury areas, significantly inhibited platelet aggregation, and significantly improved behavioural disorders after administration of HGWT. Pharmacokinetics studies indicated that rapid absorption in the blood and quick elimination time for five main constituents: paeoniflorin, albiflorin, astragaloside IV, calycosin-7-o-β-d-6-glucoside, and cinnamic acid. Moreover, HGWT was found to be safe in terms of acute toxicity (14 days) and long–term (13 weeks) administration, with no observed toxic reactions. 

Phase IV: Computational analyses 
Molecular docking was performed between 782 ligands (obtained from HGWT’s chemical compounds) and 19 receptors (identified as SRNW target proteins) using AutoDock Vina. A total of 14,858 docking results were retrieved. The average binding affinity scores of the top three target proteins among the 19 were PDE5A (−6.66 kcal/mol), ESR1 (−6.62 kcal/mol) and ADRB2 (−6.62 kcal/mol). The DZ118–ESR1 (binding affinity score: −11.1 kcal/mol) and HQ068–MAPK3 (binding affinity score: −10.4 kcal/mol) complexes were selected for the molecular dynamics simulations because their complex interactions exhibited the highest binding affinity values. 

In molecular dynamics simulations, the DZ118–ESR1 complex reached equilibrium after approximately 50 ns in terms of root mean square deviation. Differences in the RMSF of apo– and ligand–bound ESR1 were observed in regions around the residues Glu339, Arg412, Lys416 and Lys53. The average binding free energy using MM–PBSA showed two major peaks with significant binding energy contributions at Met421 (–10.74 kJ/mol) and Leu525 (–10.02 kJ/mol). 

In the HQ068–MAPK3 complex, during molecular dynamics simulations, HQ068 binds closely to the mitogen–activated protein insertion site by forming hydrogen bonds with Ser263, Leu281, Leu284, Ser286 and Lys289 in all three trajectories. This indicates HQ068 promotes mitogen– activated protein kinase insertion by stabilising its binding site. Three major peaks of average binding free energy were observed at Pro264, Gln 266 and Thr288, all of which were predicted to form close contacts with the central hydrophobic part of HQ068. These key residues contributing to the interactions likely play integral roles in the binding of selective modulators. Analyses of the pharmacokinetic and pharmacodynamic properties of the two ligands (DZ118 and HQ068) using Swiss ADME and pkCSM platforms indicated that they are well within the parameters for drug–likeness, oral bioavailability, and safety. 

Conclusions 
SRNW is the most common symptom in post–stroke patients, and HGWT has been widely used for managing SRNW in both traditional Chinese medicine and modern clinical practices. This project provides a comprehensive understanding of HGWT from traditional to modern perspectives and offers a mechanistic understanding of HGWT on SRNW using computational analysis methods. The DZ118–ESR1 and HQ068–MAPK3 complexes were predicted to be the most bioactive for SRNW. These compounds should be explored as potential agents to alleviate SRNW symptoms in future studies. Experimental studies are recommended to validate the computational results.