title: Melatonin or ramelteon therapy differentially affects hepatic gene expression profiles after haemorrhagic shock in rat--A microarray analysis.
abstract: OBJECTIVE
  Melatonin has been demonstrated to reduce liver damage in different models of stress. However, there is only limited information on the impact of this hormone on hepatic gene expression. The aim of this study was, to investigate the influence of melatonin or the melatonergic agonist ramelteon on hepatic gene expression profiles after haemorrhagic shock using a whole genome microarray analysis.
  
  
  METHODS
  Male Sprague-Dawley rats (200-300 g, n=4/group) underwent haemorrhagic shock (mean arterial pressure 35±5 mmHg). After 90 min of shock, animals were resuscitated with shed blood and Ringer's and treated with vehicle (5% dimethyl sulfoxide), melatonin or ramelteon (each 1.0 mg/kg intravenously). Sham-operated animals were treated likewise but did not undergo haemorrhage. After 2 h of reperfusion, the liver was harvested, and a whole genome microarray analysis was performed. Functional gene expression profiles were determined using the Panther® classification system; promising candidate genes were evaluated by quantitative polymerase chain reaction (PCR).
  
  
  RESULTS
  Microarray and PCR data showed a good correlation (r(2)=0.84). A strong influence of melatonin on receptor mediated signal transduction was revealed using the functional gene expression profile analysis, whereas ramelteon mainly influenced transcription factors. Shock-induced upregulation of three candidate genes with relevant functions for hepatocytes (ppp1r15a, dusp5, rhoB) was significantly reduced by melatonin (p<0.05 vs. shock/vehicle), but not by ramelteon. Two genes previously known as haemorrhage-induced (il1b, s100a8) were transcriptionally repressed by both drugs.
  
  
  CONCLUSIONS
  Melatonin and ramelteon appear to induce specific hepatic gene expression profiles after haemorrhagic shock in rats. The observed differences between both substances are likely to be attributable to a distinct mechanism of action in these agents.
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: astrid.kleber@uks.eu.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kleber
authors.affiliation: Department of Urology, Bundeswehrkrankenhaus Koblenz, Germany. Electronic address: christianruf@bundeswehr.org.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Ruf
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: alexander.wolf@uks.eu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: tobias.fink@uks.eu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fink
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Glas
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: beate.wolf@uks.eu.
authors.forename: Beate
authors.initials: B
authors.lastname: Wolf
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg (Saar), Germany. Electronic address: thomas.volk@uks.eu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Volk
authors.affiliation: Bundeswehr Institute of Radiobiology, München, Germany. Electronic address: michaelabend@bundeswehr.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Abend
authors.affiliation: Department of Anaesthesiology, Düsseldorf University Hospital, Germany. Electronic address: alexander.mathes@med.uni-duesseldorf.de.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Mathes
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D007192:Indenes / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D014408:Biomarkers, Tumor; D007192:Indenes; D012333:RNA, Messenger; C495910:ramelteon; D008550:Melatonin
keywords: Gene expression profile; Haemorrhagic shock; Melatonin; Microarray; Ramelteon