Abstract 18656: Boronated Antioxidant Prodrug (BRAP) as a Novel Hydrogen Peroxide-activatable Therapy for Ischemia-reperfusion Injury
Generation of high level of H2O2 is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. We generated boronated anti-oxidant prodrug (BRAP), designed to initially react specifically in presence of high level of H2O2 through boronic ester bond, which allows it to be targeted to oxidative stress site. This reaction results in effective scavenging of H2O2 and it releases hydroxybenzyl alcohol, which has intrinsic antioxidant and anti-inflammatory properties. BRAP significantly reduced ROS generation and elevation of inflammation markers after LPS treatment in vitro. BRAP also protected H2O2-induced cell death in adult cardiomyocytes. To explore beneficial effects of BRAP in cardiac I/R injury, cardiac function was evaluated 2 wks after I/R in mice. Pressure volume loop analysis showed that I/R resulted in a significant reduction of cardiac output and stroke work. However, daily intraperitoneal administration of BRAP (1.5 mg/kg) effectively attenuated I/R-induced cardiac dysfunction. Echocardiography also showed that BRAP increased ejection fraction and fractional shortening compared with vehicle I/R mice. Dihydroethidium staining showed BRAP significantly decreased ROS generation after I/R. In addition, BRAP decreased elevation of proinflammatory cytokines compared with vehicle I/R mice. Moreover, BRAP effectively blocked apoptosis with reduction of caspase-3 activation and TUNEL-positive cells. Since oral delivery is the most common and preferred method for long-term drug administration and BRAP is stable in acidic environment, we examined the effectiveness of oral delivery of BRAP in renal I/R injury. The elevation of serum creatinine level as a marker of renal function 24 hr after I/R was significantly reduced by oral delivery of BRAP. BRAP effectively scavenged ROS overproduction and blocked inflammation and apoptosis after I/R in kidney. In the safety profile of BRAP, there were no renal or liver functional abnormalities and no significant histological evidence of accumulated toxicity in various organs associated with administration of high dose of BRAP for 7 days. Therefore, BRAP can be used in targeted therapy for I/R injury with its protective effect of blocking oxidative stress, inflammation, and apoptosis.
Author Disclosures: D. Lee: None. S. Bae: None. S. Park: None. D. Jeong: None. M. Park: None. M.A. Samad: None. Q. Ke: None. P.M. Kang: None.
- © 2014 by American Heart Association, Inc.