Edaravone, a Novel Free Radical Scavenger, Reduces High-Mobility Group Box 1 and Prolongs Survival in a Neonatal Sepsis Model

Abstract

Free radicals play an important role in the inflammatory process of sepsis. We hypothesized that edaravone, a novel free radical scavenger, can suppress pathophysiological events and prolong survival in a neonatal sepsis cecal ligation and perforation (CLP) model. Of 32 3-day-old anesthetized and mechanically ventilated piglets, 11 received CLP only, 10 received CLP and edaravone treatment starting 30 min after CLP, and 11 constituted a sham (control) group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, serum total hydroperoxide, nitrite and nitrate, TNF-alpha, and high-mobility group box 1 (HMGB1) were measured before CLP and at 1, 3, and 6 h after CLP. Compared with the CLP group, the edaravone group showed higher MAP at 6 h, lower heart rate at 1 and 3 h, lower total hydroperoxide at 1 h, lower nitrite and nitrate at 3 and 6 h, and higher (although not significantly so) mean cardiac output at 1, 3, and 6 h. TNF-alpha elevation was delayed from 1 h in the CLP group to 3 h in the edaravone group. In the edaravone group, HMGB1 did not change significantly at any time, whereas in the CLP group, it increased at 6 h. Survival times were longer in the edaravone group than in the CLP group (15.4 +/- 1.4 vs. 10.2 +/- 1 h; P < 0.005). In addition, each of the serial dilutions of edaravone had a higher biological antioxidant potential than tempol does. In conclusion, edaravone suppressed free radicals, delayed the TNF-alpha surge, and prevented HMGB1 elevation, thereby maintaining MAP and prolonging survival time in a neonatal sepsis CLP model.

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

“…The O 2 scavenger edaravone has a suppressive effect on the release of cytokines and oxidative mediators and therefore can limit the oxidant-antioxidant imbalance associated with severe systemic inflammation and multiple organ damage in neonatal sepsis (25). This experiment demonstrated that ETR-P1/fl could similarly prevent the sepsis-induced elevation of oxidative stress mechanisms and thus improve the health of the cardiopulmonary system in neonatal sepsis.…”

Chitosan oligosaccharides protect mice from LPS challenge by attenuation of inflammation and oxidative stress

“…In recent years, some of the postulated molecular mechanisms of sepsis progression are related to the imbalance between ROS production and scavenging by the cellular anti-oxidant system [5,[34][35][36]. Lots of studies have shown that excessive production of ROS and other free radicals in sepsis, such as H 2 O 2 , superoxides and NO, which are associated with inflammation, lead to a condition of oxidative stress and contribute to high mortality rates [6,25].…”

HMGB1 in health and disease

“…H 2 O 2 actives the MAPK and NF-κB pathways, which in turn promotes HMGB1 release in macrophages and monocytes (Tang et al, 2007e). Antioxidants such as NAC (Tsung et al, 2007a), quercetin (Tang et al, 2009), edaravone (Kato et al, 2009), pyrrolidine dithiocarbamate (Zhang et al, 2010), and resveratrol (Delucchi et al, 2012) significantly inhibit HMGB1 release in several animal infection and injury models.…”