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The objective of this study was to investigate whether endoplasmic reticulum (ER<\/jats:styled-content>) stress and unfolded protein response (UPR<\/jats:styled-content>) inhibition is an underlying mechanism of melatonin anti\u2010apoptotic effects in an animal model of FHF<\/jats:styled-content> of viral origin induced by the rabbit hemorrhagic disease virus (RHDV<\/jats:styled-content>). Rabbits were experimentally infected with 2\u00a0\u00d7\u00a0104<\/jats:sup> hemagglutination units of a RHDV<\/jats:styled-content> isolate and received melatonin at two concentrations of 10\u00a0mg\/kg and 20\u00a0mg\/kg at 0\u00a0hr, 12\u00a0hr and 24\u00a0hr postinfection. RHDV<\/jats:styled-content> infection induced increased expression of CCAAT<\/jats:styled-content>\/enhancer\u2010binding protein homologous protein (CHOP<\/jats:styled-content>), immunoglobulin heavy chain binding protein (BiP<\/jats:styled-content>\/GRP<\/jats:styled-content>78), glucose\u2010regulated protein 94 (GRP<\/jats:styled-content>94), phospho\u2010c\u2010Jun N<\/jats:styled-content>\u2010terminal kinase (JNK<\/jats:styled-content>) and caspase\u201012. These effects were attenuated by melatonin. Double immunofluorescence staining showed colocalization of CHOP<\/jats:styled-content> and cleaved caspase\u20103 in liver sections of RHDV<\/jats:styled-content>\u2010infected rabbits, while immunostaining decreased markedly with melatonin treatment. RHDV<\/jats:styled-content> infection resulted in significant increases in the mRNA<\/jats:styled-content> levels of activating transcription factor 6 (ATF<\/jats:styled-content>6), ATF<\/jats:styled-content>4, inositol\u2010requiring enzyme 1 (IRE<\/jats:styled-content>1), spliced X<\/jats:styled-content>\u2010box binding protein\u20101 (XBP<\/jats:styled-content>1s) and tumor necrosis factor receptor\u2010associated factor 2 (TRAF<\/jats:styled-content>2). Melatonin attenuated the extent of the changes. Data obtained provide evidence that in rabbits with experimental infection by RHDV<\/jats:styled-content>, reduction in apoptotic liver damage by melatonin is associated with attenuation of ER<\/jats:styled-content> stress through a modulation of the three arms of UPR<\/jats:styled-content> signaling and further support a potential hepatoprotective role of melatonin in FHF<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/jpi.12063","type":"journal-article","created":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T15:57:40Z","timestamp":1367337460000},"page":"221-228","source":"Crossref","is-referenced-by-count":65,"title":["Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin"],"prefix":"10.1111","volume":"55","author":[{"given":"Mar\u00eda J.","family":"Tu\u00f1\u00f3n","sequence":"first","affiliation":[{"name":"Institute of Biomedicine (IBIOMED) University of Le\u00f3n 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