Protective effect of N-acetylcysteine on cellular energy depletion in a non-septic shock model induced by zymosan in the rat.
Recently, it was proposed that zymosan, a nonbacterial agent, causes cellular injury by inducing the production of peroxynitrite and consequent poly-(ADP-ribose) synthetase (PARS activation). Here we investigated whether in vivo N-acetylcysteine treatment inhibits cellular injury 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, and by nitrotyrosine. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, and reduction of cellular levels of NAD+. In vivo treatment with N-acetylcysteine (40, 20, and 10 mg/kg, intraperitoneally, 1 and 6 h after zymosan) significantly reduced in a dose-dependent manner peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, and the loss of cellular levels of NAD+. Our study supports the view that the antioxidant and anti-inflammatory effect of N-acetylcysteine is also correlated with the inhibition of peroxynitrite production. In conclusion, N-acetylcysteine may be a novel pharmacological approach to prevent cell injury in inflammation.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@imeuniv.unime.it
Costantino
G
G
Caputi
A P
AP
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009243:NAD / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D012769:Shock / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015054:Zymosan
D016166:Free Radical Scavengers; D009566:Nitrates; D009243:NAD; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015054:Zymosan; D000111:Acetylcysteine