The protective role of endogenous melatonin in carrageenan-induced pleurisy in the rat

Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide (NO) with the superoxide anion, was recently proposed to play a major pathogenic role in the inflammatory process. Here we have investigated the effects of endogenous melatonin, a known scavenger of peroxynitrite, in ra ts subjected to carrageenan-induced pleurisy. Endogenous melatonin was depl eted in rats maintained on 24 h light cycle for 1 wk. lit vivo depletion of endogenous melatonin enhanced the carrageenan-induced degree of pleural ex udation and polymorphonuclear leukocyte migration in rats subjected to carr ageenan-induced pleurisy. Lung myeloperoxidase activity and lipid peroxidat ion were significantly increased in melatonin-deprived rats. However, the i nducible NO synthase in lung samples was unaffected by melatonin depletion. Immunohistochemical analysis for nitrotyrosine revealed a positive stainin g in lungs from carrageenan-treated rats that was markedly enhanced in mela tonin-deprived rats. Furthermore, melatonin depletion significantly increas ed peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, enhanced DNA damage and the decrease in mitochond rial respiration and reduced the cellular levels of NAD+ in macrophages har vested from the pleural cavity of rats subjected to carrageenan-induced ple urisy. In vivo treatment with exogenous melatonin (15 mg/kg intraperitoneal ) significantly reversed the effects of melatonin depletion. Thus, endogeno us melatonin plays an important protective role against carrageenan-induced local inflammation.-Cuzzocrea, S., Tan, D.-X., Costantino, G., Mazzon, E., Caputi, A. P., Reiter, R. J. The protective role of endogenous melatonin i n carrageenan-induced pleurisy in the rat.