Optimization of Huang-Lian-Jie-Du-Decoction for Ischemic Stroke Treatment and Mechanistic Study by Metabolomic Profiling and Network Analysis.

Qian Zhang,Dingqiao Xu,Shanting Liao,Junsong Wang,Minghua Yang,Lingyi Kong,Pei Li,Yan Lv

doi:10.3389/fphar.2017.00165

Abstract

Optimal drug proportions and mechanism deciphering of multicomponent drugs are critical for developing novel therapies to cope with complex diseases, such as stroke. In the present study, orthogonal experimental design was applied to explore the optimal proportion of the four component herbs in Huang-Lian-Jie-Du-Decoction (HLJDD) on the treatment of ischemic stroke. The treatment efficacies and mechanisms were assessed using global and amino acids (AAs) targeted metabolomics, as well as correlation network analysis. The global NMR metabolomics results revealed that AAs metabolism was significantly perturbed in middle cerebral artery occlusion rats. The levels of 23 endogenous AAs were then subjected to HPLC-QTOF-MS/MS analysis. These results complemented with neurobehavioral evaluations, cerebral infarct assessments, biochemical evaluations, histological inspections and immunohistochemistry observations strongly demonstrated that HLJDD with optimal proportion of 6 (Rhizoma coptidis): 4 (Radix scutellariae): 1 (Cortex phellodendr): 3 (Fructus Gardeniae) had the best efficacy on ischemic stroke, which could be ascribed to its modulation on AA metabolism. This integrated metabolomics approach showed the potential and applicable in deciphering the complex mechanisms of traditional Chinese medicine formulae on the treatment of complicated diseases, which provided new means to assess the treatment effects of herb combinations and to further development of drugs or therapies based on these formulae.

Highlights

Stroke is one of the leading causes of death and adult disability worldwide, and ischemic stroke accounts for 87% of all forms of stroke patients (Strong et al, 2007; Lloyd-Jones et al, 2010)
According to the quantitative analysis of the infarct volumes and TTC staining of cerebral slices (Figures 1A,B), ischemia/reperfusion (I/Radix scutellariae (Rs)) significantly increased the cerebral infarct volume (37.85 ± 2.17%), which was significantly attenuated by F1, F5, and F9 treatments
I/R produced a notable reduction in the quantity of GSH in the middle cerebral artery occlusion (MCAO) group, which was reversed by F1, F5, and F9 treatments

Summary

Introduction

Stroke is one of the leading causes of death and adult disability worldwide, and ischemic stroke accounts for 87% of all forms of stroke patients (Strong et al, 2007; Lloyd-Jones et al, 2010). Increasing evidences in treating complex illness such as ischemic stroke demonstrate that treatment regimens containing multiple drugs with distinct but related mechanisms can usually amplify the therapeutic efficacies of each agent, leading to maximal therapeutic efficacy with minimal adverse effects. Combination therapies have been advocated by prescriptions in the form of formulae in traditional Chinese medicine (TCM) for more than 2,500 years to prevent and cure diseases based on clinical practice (Wang et al, 2008). It is important to elucidate the complex action mechanism of TCM formulae to improve its clinical efficacy and safety, and for further drug or therapy development (Wang et al, 2008). Understanding optimal drug proportions and synergistic mechanisms of multicomponent drugs are critical for developing novel strategies to cope with complex diseases, such as stroke

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Discussion

Conclusion