Get access

Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus

Authors

  • María J. Tuñón,

    1. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    Search for more papers by this author
  • Beatriz San Miguel,

    1. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    Search for more papers by this author
  • Irene Crespo,

    1. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    Search for more papers by this author
  • Francisco Jorquera,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    2. Gastroenterology Unit, Hospital of León, León, Spain
    Search for more papers by this author
  • Eva Santamaría,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    2. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Marcelino Alvarez,

    1. Department of Animal Health, University of León, León, Spain
    Search for more papers by this author
  • Jesús Prieto,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    2. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
    Search for more papers by this author
  • Javier González-Gallego

    1. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
    Search for more papers by this author

Address reprint requests to Javier González-Gallego, PhD, MD, Institute of Biomedicine, University of León, 24071-León, Spain.
E-mail: jgonga@unileon.es

Abstract

Abstract:  Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate the antiapoptotic effect of melatonin in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 104 hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10 and 20 mg/kg at 0, 12, and 24 hr postinfection. RHDV infection induced liver apoptosis, with increased caspase-3 immunoexpression and activity and poly(ADP-ribose)polymerase-1 (PARP-1) proteolysis. These effects were attenuated by melatonin in a concentration-dependent manner. Antia-poptotic effects of melatonin were related to a reduced expression of Bax and cytosolic cytochrome c release, increased expression of Bcl-2 and Bcl-xL, and inhibition of caspase-9 activity. Increased thiobarbituric reactive acid substances concentration and oxidized-to-reduced glutathione ratio were significantly prevented by melatonin administration. Melatonin treatment also resulted in a reduction in caspase-8 activity, tumor necrosis factor receptor-1 (TNF-R1) expression, and phosphorylated Janus kinase (JNK) expression, and increased expression of cellular FLICE-inhibitory protein (c-FLIP). Our findings show that inhibition of apoptotic mechanisms contributes to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and supports a potential hepatoprotective role of melatonin in FHF.

Get access to the full text of this article

Ancillary