Neurokinin-1 Receptor Antagonists CP-96,345 and L-733,060 Protect Mice from Cytokine-Mediated Liver Injury (original) (raw)

Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

, Gabriele Sass, Alexandra K. Kiemer, Angelika M. Vollmar, Winfried L. Neuhuber and Gisa Tiegs

Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 31-39; DOI: https://doi.org/10.1124/jpet.102.043539

Abstract

Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) ind-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2_S_,3_S_)-cis_-2-(diphenylmethyl)-N_-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2_S,3_S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFα, IFNγ, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFα and IFNγ, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.

Footnotes

• This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Grant NE 534/1-1.

• DOI: 10.1124/jpet.102.043539

• Abbreviations:
  SP
  substance P
  NF-κB
  nuclear factor-κB
  NK-1R
  neurokinin-1 receptor
  LPS
  lipopolysaccharide
  GalN
  d-galactosamine
  TNFα
  tumor necrosis factor-α
  IFNγ
  interferon-γ
  IL
  interleukin
  CP-96,345
  (2_S_,3_S_)-cis_-2-(diphenylmethyl)-N_-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine
  L-733,060
  (2_S,3_S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine
  ALT
  alanine aminotransferase
  AST
  aspartate aminotransferase
  NPC
  nonparenchymal liver cells
  RT-PCR
  reverse transcription-polymerase chain reaction
  bp
  base pair
  DTT
  dithiothreitol
  AP-1
  activator protein-1
  TBS
  Tris-buffered saline
  SR 140333
  nolpitantium

• • Received August 27, 2002.
  • Accepted December 19, 2002.

• The American Society for Pharmacology and Experimental Therapeutics

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