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Y-40138, a multiple cytokine production modulator, protects against D-galactosamine and lipopolysaccharide-induced hepatitis.

Abstract
Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs are associated with tumor necrosis factor (TNF) production. D-Galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure. In this model, TNF-alpha plays a central role in the pathogenesis of D-GalN/LPS-induced liver injury in mice. Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl inhibits TNF-alpha and augments interleukin (IL)-10 production in LPS-injected mice in plasma. In the present study, we examined the effect of Y-40138 on D-GalN/LPS-induced hepatitis. Y-40138 (10mg/kg, i.v.) significantly suppressed TNF-alpha and monocyte chemoattractant protein-1 (MCP-1) production and augmented IL-10 production in plasma. In addition, Y-40138 significantly inhibited TNF-alpha production induced by direct interaction between human T lymphocytes and macrophages. Y-40138 suppressed plasma alanine transaminase (ALT) elevation and improved survival rate in D-GalN/LPS-injected mice, and it is suggested that the protective effect of Y-40138 on hepatitis may be mediated by inhibition of TNF-alpha and MCP-1, and/or augmentation of IL-10. This compound is expected to be a new candidate for treatment of cytokine and/or chemokine-related liver diseases such as alcoholic hepatitis.
AuthorsTetsuko Fukuda, Akira Mogami, Hideki Tanaka, Tsutomu Yoshikawa, Masao Hisadome, Hirotsugu Komatsu
JournalLife sciences (Life Sci) Vol. 79 Issue 9 Pg. 822-7 (Jul 24 2006) ISSN: 0024-3205 [Print] Netherlands
PMID16626762 (Publication Type: Journal Article)
Chemical References
  • Acetamides
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokines
  • Cytokines
  • Lipopolysaccharides
  • Piperazines
  • Tumor Necrosis Factor-alpha
  • Y 39041
  • Galactosamine
  • Alanine Transaminase
Topics
  • Acetamides (pharmacology)
  • Alanine Transaminase (blood)
  • Animals
  • Cell Death (drug effects)
  • Chemical and Drug Induced Liver Injury (pathology, prevention & control)
  • Chemokine CCL2 (biosynthesis)
  • Chemokines (biosynthesis)
  • Coculture Techniques
  • Cytokines (biosynthesis, blood)
  • Female
  • Galactosamine (antagonists & inhibitors, toxicity)
  • Hepatocytes (pathology)
  • Lipopolysaccharides (antagonists & inhibitors, toxicity)
  • Liver (pathology)
  • Macrophages (drug effects, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Piperazines (pharmacology)
  • T-Lymphocytes (drug effects, metabolism)
  • Tumor Necrosis Factor-alpha (biosynthesis)

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