Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis.
OBJECTIVE
Oxidative stress plays an important role in the development of multiple organ failure and septic shock. Here we have evaluated the effects of a combination of antioxidants (N-acetylcysteine plus deferoxamine) in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP).


METHODS
Prospective, randomized, controlled experiment.


METHODS
Animal basic science laboratory.


METHODS
Male Wistar rats, weighing 300-350 g.


METHODS
Rats subjected to CLP were treated with either N-acetylcysteine (20 mg/kg, 3 hrs, 6 hrs, 12 hrs, 18 hrs, and 24 hrs after CLP, subcutaneously) plus deferoxamine (20 mg/kg, 3 hrs and 24 hrs after CLP, subcutaneously) or vehicle with or without "basic support" (saline at 50 mL/kg immediately and 12 hrs after CLP plus ceftriaxone at 30 mg/kg and clindamycin 25 mg/kg every 6 hrs).


RESULTS
After 12 hrs, tissue myeloperoxidase (indicator of neutrophil infiltration), thiobarbituric acid reactive species (as a marker of oxidative stress), catalase and superoxide dismutase activities (antioxidant enzymes), and mitochondrial superoxide production (index of uncoupling of electron transfer chain) were measured in major organs involved in septic response. Rats treated with antioxidants had significantly lower myeloperoxidase activity and thiobarbituric acid reactive species formation in all organs studied. Mitochondrial superoxide production was significantly reduced by antioxidant treatment. Furthermore, antioxidants significantly improved the balance between catalase and superoxide dismutase activities. Survival in untreated septic rats was 10%. Survival increased to 40% with fluids and antibiotics. In rats treated only with N-acetylcysteine plus deferoxamine, survival was also significantly improved (47%) in a manner similar to basic support. Survival increased to 66% with basic support with N-acetylcysteine plus deferoxamine.


CONCLUSIONS
Our data provide the first experimental demonstration that N-acetylcysteine plus deferoxamine reduces the consequences of septic shock induced by CLP in the rat, by decreasing oxidative stress and limiting neutrophil infiltration and mitochondrial dysfunction, thereby improving survival.
Ritter
Cristiane
C
Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catariense, Circiúma, Brazil.
Andrades
Michael E
ME
Reinke
Adalisa
A
Menna-Barreto
Sérgio
S
Moreira
José Cláudio F
JC
Dal-Pizzol
Felipe
F
D000111:Acetylcysteine / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D003676:Deferoxamine / Q000008:administration & dosage* / Q000494:pharmacology; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate
D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D003676:Deferoxamine; D000111:Acetylcysteine