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 synthase (NOS) is an important contributing factor for the development of cardiovascular collapse and subsequent death in endotoxic shock. Diethyldithiocarbamate (DETC) is a molecular scavenger of NO and can inhibit overexpression of a number of cytokines during shock through inactivation of transcription factors such as nuclear factor (NF)-kappaB. Thus, DETC may be a useful 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 (intraperitoneal: 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 endotoxic mice were effective in increasing survival time when compared with untreated animals and DETC pretreatment was more effective than methylprednisolone (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 metalloproteinases such as gelatinase A and B which may be responsible for cellular release of cytokines. These results indicate that DETC and its analogs may be useful in the treatment of endotoxic shock.
Kishnani
N S
NS
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260-1200, USA.
Tabrizi-Fard
M A
MA
Fung
H L
HL
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D017364:Collagenases / Q000097:blood / Q000187:drug effects; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018093:Gelatinases / Q000097:blood / Q000187:drug effects; D008070:Lipopolysaccharides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000097:blood / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002614:Chelating Agents; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D004050:Ditiocarb; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9