Compound Danshen Dripping Pill ameliorates post ischemic myocardial inflammation through synergistically regulating MAPK, PI3K/AKT and PPAR signaling pathways

Compound Danshen Dripping Pill (CDDP), composed of Salvia miltiorrhiza Bunge, Panax notoginseng (Burkill) F.H. Chen and Borneol, is a famous traditional Chinese medicine formula which has made great achievements in the treatment of ischemic heart disease, but the profound mechanism of CDDP improving post ischemic myocardial inflammation hasn't been clearly discussed.The aim of this study was to explore the biological mechanism of constituents in CDDP synergistically improving post ischemic myocardial inflammation.The pharmacologic studies were applied to assess the cardio protection effect of CDDP in acute myocardial ischemic rats. To identify the anti-inflammatory ingredients in CDDP, an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-luciferase reporter assay for NF-κB inhibition were used. The network pharmacology and molecular docking assay were adopted to predict targets of anti-inflammatory ingredients and then the regulation effects of these active components on their targets were also verified.Our results indicated that CDDP exerted an excellent cardio protection effect by reversing echocardiographic abnormalities, attenuating histopathological lesion, ameliorating circulating myocardial markers and inflammation cytokines. Tanshinol, salvianolic acid B (Sal B), tanshinone IIA (Tan IIA) and notoginsenoside R1 (NGR1) were the pivotal anti-inflammatory ingredients in CDDP. The anti-inflammatory mechanism is that tanshinol and Sal B respectively targeted on PPARγ and JNK, while Tan IIA worked on AKT1 and NGR1 bound to PI3K.Our results firstly demonstrated that CDDP effectively ameliorated post ischemic myocardial inflammation through simultaneously modulating MAPK, PI3K/AKT and PPAR pathways in a multi-components synergetic manner.