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Salvage effect of E5564, Toll-like receptor 4 antagonist on d-galactosamine and lipopolysaccharide-induced acute liver failure in rats.

AbstractBACKGROUND AND AIMS:
The transmembrane protein Toll-like receptor 4 (TLR4), which exists mainly in macrophages such as Kupffer cells of the liver, plays an important role in recognizing and mediating macrophage activation and pro-inflammatory cytokine release. Activation of the pro-inflammatory cytokine cascade, including tumor necrosis factor-alpha (TNF-alpha), has a pivotal role in the progression of severe liver injury. D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced liver injury in rats is an experimental model of fulminant hepatic failure, where TNF-alpha plays a central role in the progression of liver injury. E5564, a synthetic analogue of the lipid A component of endotoxin, inhibits endotoxin-stimulated inflammation and is under study for patients with sepsis. In the present study, we sought to explore the salvage effect of TLR4 antagonist E5564 on GalN+LPS-induced acute liver failure (ALF) in rats.
METHODS:
ALF was induced in male Wistar rats by the intraperitoneal injection of GalN (500 mg/kg) and LPS (50 microg/kg). Immediately after GalN+LPS injection, rats were treated with intravenous injection of E5564 (3 mg/kg). The cumulative survival rates of GalN+LPS-induced ALF rats were compared between those with and without E5564 treatment.
RESULTS:
The intravenous injection of E5564 reduced the elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase and TNF-alpha levels in rats at 3 h after GalN+LPS injection, and improved the survival rate of GalN+LPS-induced ALF rats at 24 h (8% vs 43%).
CONCLUSIONS:
TLR4 antagonist E5564 reduced GalN+LPS-induced acute liver injury in rats and improved the overall survival rate of GalN+LPS-induced ALF rats. It may contribute to the treatment of ALF through blocking endotoxin-induced TNF-alpha overproduction of macrophages.
AuthorsToshiyuki Kitazawa, Tatsuhiro Tsujimoto, Hideto Kawaratani, Hiroshi Fukui
JournalJournal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 25 Issue 5 Pg. 1009-12 (May 2010) ISSN: 1440-1746 [Electronic] Australia
PMID20546456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers
  • E5564
  • Lipid A
  • Lipopolysaccharides
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • lipopolysaccharide, E coli O55-B5
  • Galactosamine
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Bilirubin
Topics
  • Alanine Transaminase (blood)
  • Animals
  • Aspartate Aminotransferases (blood)
  • Bilirubin (blood)
  • Biomarkers (blood)
  • Disease Models, Animal
  • Galactosamine
  • Injections, Intravenous
  • Lipid A (administration & dosage, analogs & derivatives, pharmacology)
  • Lipopolysaccharides
  • Liver (drug effects, immunology, pathology)
  • Liver Failure, Acute (chemically induced, drug therapy, immunology)
  • Male
  • Rats
  • Rats, Wistar
  • Time Factors
  • Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)
  • Tumor Necrosis Factor-alpha (blood)

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