Diethyldithiocarbamate prolongs survival of mice in a lipopolysaccharide-induced endotoxic shock model: Evidence for multiple mechanisms

It is now known that overproduction of nitric oxide (NO) by nitric oxide sy nthase (NOS) is an important contributing factor for the development of car diovascular collapse and subsequent death in endotoxic shock. Diethyldithio carbamate (DETC) is a molecular scavenger of NO and can inhibit overexpress ion of a number of cytokines during shock through inactivation of transcrip tion factors such as nuclear factor (NF)-kappa B. Thus, DETC may be a usefu l adjunct in the therapy of endotoxic shock. In our study, we examined the effect of DETC on survival time in a murine model of severe endotoxic shock . Our results indicated that selected in vivo dosage regimens of DETC (intr aperitoneal: at -2, -1, 3, 6, and 10 h or at -2, -1,3, 6, 9, 12, 15, and 18 h relative to lipopolysaccharide administration, 180 mg/kg, at t = 0) in e ndotoxic mice were effective in increasing survival time when compared with untreated animals and DETC pretreatment was more effective than methylpred nisolone (p < .05). DETC was shown to exert multiple beneficial mechanisms, including 1) a decrease in circulating NO, as determined by plasma nitrite /nitrate levels, 2) a reduction in plasma tumor necrosis factor-alpha after lipopolysaccharide induction, and 3) decreased expressions of metalloprote inases such as gelatinase A and B which may be responsible for cellular rel ease of cytokines. These results indicate that DETC and its analogs may be useful in the treatment of endotoxic shock.