Effect of lazaroid U-74389G and methylprednisolone on endotoxin-induced shock in mice.
BACKGROUND
Lazaroids are nonglucocorticoid analogs of methylprednisolone with multiple actions. We investigated whether lazaroid U-74389G could attenuate endotoxin-induced liver injury. We hypothesized that U-74389G treatment 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 intraperitoneally) was administered to male ICR mice, and U-74389G (3 mg/kg intraperitoneally) or methylprednisolone (30 mg/kg intravenously) was administered simultaneously. 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 against lipopolysaccharide-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, tumor necrosis factor-alpha, and inducible nitric oxide synthase messenger RNA formation, hepatic enzyme release, and neutrophil infiltration in the liver. U-74389G and methylprednisolone also showed inhibitory effects on NF-kappa B activation in the liver.


CONCLUSIONS
These findings suggest that U-74389G can suppress proinflammatory gene up-regulation through inhibition of NF-kappa B activation and that it is a promising new antioxidant drug for the treatment of endotoxin shock.
Fukuma
K
K
Department of Surgery II, Hiroshima University School of Medicine, Japan.
Marubayashi
S
S
Okada
K
K
Yamada
K
K
Kimura
A
A
Dohi
K
K
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000032:analysis; D015152:Blotting, Northern; D015342:DNA Probes; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010587:Phagocytosis / Q000276:immunology; D011281:Pregnatrienes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012769:Shock / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015342:DNA Probes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D011281:Pregnatrienes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C074965:U 74389F; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008775:Methylprednisolone