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

Life Sciences
Tetsuko FukudaHirotsugu Komatsu

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. ...Continue Reading

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Citations

Aug 24, 2007·Clinical and Experimental Pharmacology & Physiology·Herman ChanMichael S-C Tam
Jan 22, 2011·Journal of Gastroenterology and Hepatology·Hideto KawarataniHiroshi Fukui
Nov 26, 2009·World Journal of Gastroenterology : WJG·Tatsuhiro TsujimotoHiroshi Fukui
Apr 16, 2013·Biochemical and Biophysical Research Communications·Xiao LiuJiong Li
Sep 11, 2007·European Journal of Pharmacology·Tsuyoshi YoshidaHideo Inoue
Dec 31, 2009·European Journal of Clinical Investigation·L-M LiuJ Luo
May 11, 2019·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Xiao WangWanyu Shi
Mar 26, 2015·World Journal of Gastroenterology : WJG·Liang-Ming LiuTong Zhu
Mar 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qihui LuoZhengli Chen

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