Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in carrageenan-induced pleurisy.
Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of NO with superoxide anion, has been proposed to have major pathogenetic role in inflammatory process. Here we have investigated the therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a novel superoxide dismutase mimetic that possesses peroxynitrite scavenging effect, in rats subjected to carrageenan-induced pleurisy. In vivo treatment with MnTBAP (3 and 10 mg/kg 5 min before carrageenan) prevented in a dose-dependent manner the carrageenan-induced the degree of pleural exudation, polymorphonuclear migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and histological organ injury was significantly reduced by MnTBAP. However, MnTBAP did not inhibit the inducible NO synthase in lung samples. Immunohistochemical analysis for nitrotyrosine, a footprint of peroxynitrite, revealed a positive staining in lungs from carrageenan-treated rats. No positive nitrotyrosine staining was found in the lungs of the carrageenan-treated rats that received MnTBAP (10 mg/kg) treatment. In addition, in vivo MnTBAP treatment significantly reduced in a dose-dependent manner peroxynitrite formation as measured by the oxidation of the fluorescent dye 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. Our study demonstrates that the MnTBAP exerts multiple protective effects in carrageenan-induced pleurisy. We suggest peroxynitrite produced during the inflammatory process trigger DNA strand breakage and subsequent cellular dysfunction. Part of these anti-inflammatory effects may be related to: (1) reduction of superoxide formation due to the superoxide dismutase-like activity of the compound and (2) scavenging of peroxynitrite.
Cuzzocrea
S
S
Institute of Pharmacology, University of Messina, Italy. salvator@imeuniv.unime.it
Zingarelli
B
B
Costantino
G
G
Caputi
A P
AP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D004249:DNA Damage; D004734:Energy Metabolism / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D009566:Nitrates; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; D002351:Carrageenan; D013482:Superoxide Dismutase