TP-58, a novel thienopyridine derivative, protects mice from concanavalinA-induced hepatitis by suppressing inflammation

Cell Physiol Biochem. 2012;29(1-2):31-40. doi: 10.1159/000337584. Epub 2012 Mar 1.

Abstract

Hepatitis represents a ubiquitous human health problem but effective therapies with limited side effects are still lacking. In this study, we investigated the effect and mechanism of TP-58, a novel thienopyridine derivative, on a murine fulminant hepatitis model induced by concanavalin A (ConA). We found TP-58 markedly alleviated ConA-caused liver injury and increased survival ratio of mice injected with a lethal dose of ConA. Oral administration of TP-58 significantly alleviated ConA-caused liver injury in mice by the reduction of serum aminotransferases and liver necrosis.The analysis of proinflammatory cytokines showed that TP-58 decreased both hepatic mRNA expressions and serum protein levels of TNF-α and IL-6. And the result from LPS-stimulated RAW 264.7 cells showed TP-58 suppressed the production of TNF-α, IL-6, and Nitro Oxide (NO) in the supernatant of LPS-stimulated RAW 264.7 cells. The study of activation of nuclear factor-κB (NF-κB) by electrophoretic mobility shift assay (EMSA) showed that TP-58 inhibited the activation of NF-κB both in vivo and in vitro. The inhibitory effect was also accompanied by a parallel reduction of IκB phosphorylation. These results indicate that TP-58 protects against liver injury by inhibition of the NF-κB-mediated inflammation and suggest a potential role of TP-58 against acute liver injury and other inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Concanavalin A
  • Cytokines / blood
  • Cytokines / genetics
  • Disease Models, Animal
  • Female
  • I-kappa B Proteins / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Interleukin-6 / blood
  • Interleukin-6 / genetics
  • Lipopolysaccharides
  • Liver / drug effects*
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Thiophenes / therapeutic use
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • I-kappa B Proteins
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • Pyridines
  • Thiophenes
  • Tumor Necrosis Factor-alpha
  • Concanavalin A
  • Nitric Oxide
  • Proto-Oncogene Proteins c-akt