Beneficial effects of raxofelast (IRFI 016), a new hydrophilic vitamin E-like antioxidant, in carrageenan-induced pleurisy

1 Peroxynitrite is a strong oxidant that results from reaction between NO a nd superoxide. It has been recently proposed that peroxynitrite plays a pat hogenetic role in inflammatory processes. Here we have investigated the the rapeutic efficacy of raxofelast, a new hydrophilic vitamin E-like antioxida nt agent, in rats subjected to carrageenan-induced pleurisy. 2 In vivo treatment with raxofelast (5, 10, 20 mg kg(-1) intraperitoneally 5 min before carrageenan) prevented in a dose dependent manner carrageenan- induced pleural exudation and polymorphonuclear migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and m alondialdehyde (MDA) levels, as well as histological organ injury were sign ificantly reduced by raxofelast. 3 Immunohistochemical analysis for nitrotyrosine, a footprint of peroxynitr ite, revealed a positive staining in lungs from carrageenan-treated rats. N o positive nitrotyrosine staining was found in the lungs of the carrageenan -treated rats, which received raxofelast (20 mg kg(-1)) treatment. 4 Furthermore, in vivo raxofelast (5, 10, 20 mg kg(-1)) treatment significa ntly reduced peroxynitrite formation as measured by the oxidation of the fl uorescent dihydrorhodamine 123, prevented the appearance of DNA damage, the decrease in mitochondrial respiration and partially restored the cellular level of NAD(+) in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. 5 In conclusion, our study demonstrates that raxofelast, a new hydrophilic vitamin E-like antioxidant agent, exerts multiple protective effects in car rageenan-induced acute inflammation.