Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

Abstract

Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries.

Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia‐Reperfusion Injury

“…The most efficient way to ameliorate oxidative stress is replenishing ROS-scavenging antioxidants [17]. SOD is a common antioxidant, which is wildly distributed within mammalian organisms [51].…”

“…The in vivo hepatic I/R model was performed as previously described [3, 16, 17, 25]. Male C57BL/6 mice, aged 8–12 weeks, were purchased from Beijing University (Beijing, China) and maintained on a chow diet in a 12 h light/12 h dark environment at 25°C in the Animal Care Facility of Tongji Medical College.…”

“…H 2 O 2 is the most abundant and stable ROS. It leads to oxidative stress and is implicated in a variety of inflammatory diseases [16, 17]. H 2 O 2 can be converted into hydroxyl radicals, which are extremely reactive and more toxic than other ROS [8, 9].…”

“…Treatment with superoxide dismutase (SOD) and catalase (CAT) reduces the ROS levels, as SOD rapidly dismutases the superoxide (O 2 − ) to H 2 O 2 , and CAT scavenges H 2 O 2 to produce water, which reduces the severity of oxidative stress [5]. Beside SOD and CAT, a variety of compounds and biomaterials has been developed as potential therapeutic agents for I/R injury [6, 17]. However, it still lacks efficient, specific, and sensitive biomarkers for the accurate evaluation of the severity of oxidative stress in hepatic I/R injury [19].…”

Emodin protects against oxidative stress and apoptosis in HK-2 renal tubular epithelial cells after hypoxia/reoxygenation

“…Renal ischemia/reperfusion (I/R) injury typically occurs after renal transplantation and surgery, and is a leading cause of acute renal failure (1). Although reperfusion is a necessary approach to improve the survival probability of ischemic tissue, reperfusion itself can lead to additional cell injury, largely through the production of excessive reactive oxygen species (ROS) (2).…”