Effect of melatonin on cellular energy depletion mediated by peroxynitriteand poly (ADP-ribose) synthetase activation in an acute model of inflammation

DNA single-strand breakage and activation of the nuclear enzyme poly (ADP-r ibose) synthetase (PARS) triggers an energy-consuming. inefficient repair c ycle, which contributes to peroxynitrite-induced cellular injury. Recently, we proposed that during an acute model (pleurisy), cellular injury is medi ated by peroxynitrite formation and consequent PARS activation. Here, we in vestigated whether in vivo melatonin treatment inhibits cellular injury ind uced by peroxynitrite production and PARS activation in macrophages collect ed from rats subjected to carrageenan-induced pleurisy. Macrophages harvest ed from the pleural cavity exhibited a significant production of peroxynitr ite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 1 23. Furthermore, carrageenan-induced pleurisy caused a suppression of macro phage mitochondrial respiration, DNA strand breakage, activation of PARS, a nd reduction of cellular levels of NAD(+). In vivo treatment with melatonin [12.5 or 25 or 50 mg/kg, intraperitoneally (i.p.), 30 min before carrageen an] significantly reduced peroxynitrite: formation in a dose-dependent mann er and prevented the appearance of DNA damage, decrease in mitochondrial re spiration, loss of cellular levels of NAD(+), and PARS activation. Our stud y supports the view that the antioxidant and anti-inflammatory effect of me latonin is also correlated with the inhibition of peroxynitrite production and PARS activation. In conclusion. melatonin may be a novel pharmacologica l approach to prevent cell injury in acute inflammation.