Effect of lazaroid U-74389G and methylprednisolone on endotoxin-induced shock in mice

Background. Lazaroids are nonglucocorticoid analogs of methylprednisolone w ith multiple actions. We investigated whether lazaroid U-74389G could atten uate endotoxin-induced liver injury. We hypothesized that U-74389G treatmen t may protect against hepatic injury by suppressing proinflammatory gene up -regulation through inhibition of activation of nuclear factor kappa B (NF- kappa B). We also compared the efficacy of U-74389G with methylprednisolone in endotoxin-induced liver injury. Methods. Lipopolysaccharide (Escherichia coli, 30 mg/kg given intraperitone ally) was administered to male ICR mice, and U-74389G (3 mg/kg intraperiton eally) or methylprednisolone (30 mg/kg intravenously) was administered simu ltaneously. Phosphate-buffered saline solution (0.15 mL intravenously) was administered to mice that served as a control group. Results. U-74389G and methylprednisolone treatment significantly increased survival rates 48 hours after lipopolysaccharide injection and protected ag ainst lipopolysaccharide-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, tumor necrosis factor-alpha, and indu cible nitric oxide synthase messenger RNA formation, hepatic enzyme release , and neutrophil infiltration in the liver. U-74389G and methylprednisolone also showed inhibitory effects of NF-kappa B activation in the liver. Conclusions. These findings suggest that U-74389G can suppress proinflammat ory gene up-regulation through inhibition of NF-kappa B activation and that it is a promising new antioxidant drug for the treatment of endotoxin shoc k.