AUTHOR=Ma Chongyang , Wang Xueqian , Xu Tian , Zhang Shuang , Liu Shuling , Zhai Changming , Wang Zisong , Mu Jie , Li Changxiang , Cheng Fafeng , Wang Qingguo 

TITLE=An Integrative Pharmacology-Based Analysis of Refined Qingkailing Injection Against Cerebral Ischemic Stroke: A Novel Combination of Baicalin, Geniposide, Cholic Acid, and Hyodeoxycholic Acid

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00519

DOI=10.3389/fphar.2020.00519

ISSN=1663-9812

ABSTRACT=Stroke is the second leading cause of death after heart disease globally and Cerebral ischemic stroke accounts for approximately 70% of all incident stroke cases. We selected four main compounds from a patent Chinese medicine, Qingkailing (QKL) injection, including baicalin from Scutellariae radix (HuangQin), geniposide from Gardeniae fructus (Zhizi), and cholic acid and hyodeoxycholic acid from Bovis Calculus (Niuhuang) with a ratio of 4.4:0.4:3:2.6 m/m, to develop a more efficacious and safer modern Chinese medicine injection, refined QKL (RQKL), to treat cerebral ischemic stroke. In this study, we investigated multiple targets, levels, and pathways of RQKL by using an integrative pharmacology combining experimental validation approach. In silica study showed that RQKL may regulate PI3K-Akt, estrogen, neurotrophin, HIF-1, MAPK, Hippo, FoxO, TGF-beta, NOD-like receptor, apoptosis, NF-kappa B, Wnt, Chemokine, TNF, Toll-like receptor signaling pathways against ischemic stroke. The experimental results showed that RQKL improved neurological function and prevented infract volume and blood-brain-barrier damage. RQKL inhibited microgliosis and astrogliosis, and protected neurons from ischemic/reperfusion injury. RQKL also inhibited cell apoptosis and affecting the ratio of the anti-apoptosis protein B-cell lymphoma-2 (Bcl2) and pro-apoptosis protein Bcl2-associated X protein (Bax). Western blot analysis showed that RQKL activated AKT/PI3K signaling pathway and antibody array showed RQKL inhibited inflammatory response and decreased proinflammatory factor Tnf, Il6 and Il1b, and chemokines Ccl2, Cxcl2 and Cxcl3, and increased anti-inflammatory cytokine Il10. In conclusion, RQKL protected tissue against ischemic stroke through multiple-target, multiple signals and modulating multiple cell-types in brain. This study not only promoted our understanding of the role of RQKL against ischemic stroke, but also provided a pattern for the study of Chinese medicine combining pharmaceutical Informatics and system biology methods.