Mechanisms dissection of the combination GRS derived from ShengMai preparations for the treatment of myocardial ischemia/reperfusion injury

Ethnopharmacological relevance: Recently, a new drug combination GRS comprising ginsenoside Rbl (G-Rbl), ruscogenin (R-Rus) and schisandrin (S-SA) was screened based on ShengMai preparations, which exhibited a prominent cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury. Aim of the study: To investigate their systemic and individual mechanism of each compound in combination GRS. Materials and methods: The mice model of MI/R and hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury were performed to explore the respective characteristics of each compound in GRS against myocardial injury. Results: Each component in the combination GRS attenuated MI/R injury as evidenced by decreased myocardial infarct size, ameliorated histological features, and improved biochemical indicators. Meanwhile, ingredient G, R and S in combination also individually performed a significant decrease of apoptotic index in MI/R mice and H/ R-induced cardiomyocytes injury. Mechanistically, component G in GRS could markedly increase the ATP content in cardiomyocytes through activation of AMPK alpha phosphorylation. Interestingly, the anti-apoptotic actions of G were profoundly attenuated by knockdown of AMPK alpha, while no alteration was observed on composition R and S. Moreover, component R in GRS significantly reduced the IL-6 and TNF-alpha mRNA expression, as well as the content of IL-6 via the modulation of NF-kappa B signaling pathway. Further, component S exhibited the most powerful anti -oxidative capacity in GRS and remarkably decreased the production of MDA and ROS, and potential mechanisms might at least in part through activating the Akt-14-3-3 signaling pathway and inhibiting the phosphorylation of Bad and ERK1/2. Conclusions: Our results indicated that the respective mechanism of each compound in combination GRS against MI/R injury might closely associated with energy metabolism modulation, suppression of inflammation and oxidative stress.