Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury.
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Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. / Bang, Renate; Sass, Gabriele; Kiemer, Alexandra K; Vollmar, Angelika M; Neuhuber, Winfried L; Tiegs, Gisa.
In: J PHARMACOL EXP THER, Vol. 305, No. 1, 1, 2003, p. 31-39.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury.
AU - Bang, Renate
AU - Sass, Gabriele
AU - Kiemer, Alexandra K
AU - Vollmar, Angelika M
AU - Neuhuber, Winfried L
AU - Tiegs, Gisa
PY - 2003
Y1 - 2003
N2 - 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) in D-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-alpha (TNFalpha) and interferon-gamma (IFNgamma) 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., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)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 TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, 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.
AB - 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) in D-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-alpha (TNFalpha) and interferon-gamma (IFNgamma) 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., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)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 TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, 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.
KW - Animals
KW - Time Factors
KW - Mice
KW - Mice, Inbred BALB C
KW - Molecular Sequence Data
KW - Base Sequence
KW - Dose-Response Relationship, Drug
KW - Cytokines/metabolism
KW - Lipopolysaccharides
KW - Capsaicin/pharmacology
KW - Drug-Induced Liver Injury
KW - Liver Diseases/prevention & control
KW - Biphenyl Compounds/therapeutic use
KW - Gene Expression/drug effects
KW - Neurons, Afferent/drug effects/physiology
KW - Piperidines/therapeutic use
KW - RNA, Messenger/analysis/drug effects
KW - Receptors, Neurokinin-1/antagonists & inhibitors
KW - Sequence Homology, Nucleic Acid
KW - Transcriptional Activation/drug effects
KW - Animals
KW - Time Factors
KW - Mice
KW - Mice, Inbred BALB C
KW - Molecular Sequence Data
KW - Base Sequence
KW - Dose-Response Relationship, Drug
KW - Cytokines/metabolism
KW - Lipopolysaccharides
KW - Capsaicin/pharmacology
KW - Drug-Induced Liver Injury
KW - Liver Diseases/prevention & control
KW - Biphenyl Compounds/therapeutic use
KW - Gene Expression/drug effects
KW - Neurons, Afferent/drug effects/physiology
KW - Piperidines/therapeutic use
KW - RNA, Messenger/analysis/drug effects
KW - Receptors, Neurokinin-1/antagonists & inhibitors
KW - Sequence Homology, Nucleic Acid
KW - Transcriptional Activation/drug effects
M3 - SCORING: Journal article
VL - 305
SP - 31
EP - 39
JO - J PHARMACOL EXP THER
JF - J PHARMACOL EXP THER
SN - 0022-3565
IS - 1
M1 - 1
ER -
