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

SALVATORE CUZZOCREA^*1, DUN-XIAN TAN, GIUSEPPINA COSTANTINO^*, EMANUELA MAZZON, ACHILLE P. CAPUTI^* and RUSSEL J. REITER

^* Institute of Pharmacology, University of Messina, Italy;
Department of Cellular and Structural Biology, The University of Texas Health Center at San Antonio, San Antonio, Texas, USA; and
Biomorphology School of Medicine, University of Messina, Italy

¹Correspondence: Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi-98100, Messina, Italy. E-mail: salvator{at}www..unime.it

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 rats subjected to carrageenan-induced pleurisy. Endogenous melatonin was depleted in rats maintained on 24 h light cycle for 1 wk. In vivo depletion of endogenous melatonin enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase activity and lipid peroxidation were significantly increased in melatonin-deprived rats. However, the inducible NO synthase in lung samples was unaffected by melatonin depletion. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from carrageenan-treated rats that was markedly enhanced in melatonin-deprived rats. Furthermore, melatonin depletion significantly increased peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, enhanced DNA damage and the decrease in mitochondrial respiration and reduced the cellular levels of NAD+ in macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. In vivo treatment with exogenous melatonin (15 mg/kg intraperitoneal) significantly reversed the effects of melatonin depletion. Thus, endogenous 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 in carrageenan-induced pleurisy in the rat.

Key Words: inflammation • nitric oxide • peroxynitrite • superoxide • hydroxyl radical

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