Protective effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in a non-septic shock model induced by zymosan in the rat

Abstract: DNA single-strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Recently it was proposed that zymosan, a non-bacterial agent, causes cellular injury by inducing the production of peroxynitrite and consequent PARS activation. Here we investigated whether in vivo melatonin treatment inhibits cellular injury induced by peroxynitrite production and PARS activation in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS and reduction of cellular levels of NAD⁺. In vivo treatment with melatonin (25 and 50 mg/kg, intraperitoneally, 1 hr after zymosan injection) significantly reduced in dose-dependent manner peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, the loss of cellular levels of NAD⁺, and the PARS activation. Our study supports the view that the antioxidant and antiinflammatory effect of melatonin is also correlated with the inhibition of peroxynitrite production and PARS activation. In conclusion, melatonin may be a novel pharmacological approach to prevent cell injury in inflammation.