Salvianolic Acid B Improves Postresuscitation Myocardial and Cerebral Outcomes in a Murine Model of Cardiac Arrest: Involvement of Nrf2 Signaling Pathway

Abstract

Survival and outcome of cardiac arrest (CA) are dismal despite improvements in cardiopulmonary resuscitation (CPR). Salvianolic acid B (Sal B), extracted from Salvia miltiorrhiza, has been investigated for its cardioprotective properties in cardiac remodeling and ischemic heart disease, but less is known about its role in CA. The aim of this study was to learn whether Sal B improves cardiac and neurologic outcomes after CA/CPR in mice. Female C57BL/6 mice were subjected to eight minutes of CA induced by an intravenous injection of potassium chloride (KCl), followed by CPR. After 30 seconds of CPR, mice were blindly randomized to receive either Sal B (20 mg/kg) or vehicle (normal saline) intravenously. Hemodynamic variables and indices of left ventricular function were determined before CA and within three hours after CPR, the early postresuscitation period. Sal B administration resulted in a remarkable decrease in the time required for the return of spontaneous circulation (ROSC) in animals that successfully resuscitated compared to the vehicle-treated mice. Myocardial performance, including cardiac output and left ventricular systolic (dp/dtmax) and diastolic (dp/dtmin) function, was clearly ameliorated within three hours of ROSC in the Sal B-treated mice. Moreover, Sal B inhibited CA/CPR-induced cardiomyocyte apoptosis and preserved mitochondrial morphology and function. Mechanistically, Sal B dramatically promoted Nrf2 nuclear translocation through the downregulation of Keap1, which resulted in the expression of antioxidant enzymes, including HO-1 and NQO1, thereby counteracted the oxidative damage in response to CA/CPR. The aforementioned antiapoptotic and antioxidant effects of Sal B were impaired in the setting of gene silencing of Nrf2 with siRNA in vitro model. These improvements were associated with better neurological function and increased survival rate (75% vs. 40%, p<0.05) up to 72 hours postresuscitation. Our findings suggest that the administration of Sal B improved cardiac function and neurological outcomes in a murine model of CA via activating the Nrf2 antioxidant signaling pathway, which may represent a novel therapeutic strategy for the treatment of CA.