title: Long-term oral melatonin administration reduces ethanol-induced increases in duodenal mucosal permeability and motility in rats.
abstract: OBJECTIVE
  Increased intestinal epithelial permeability is associated with intestinal inflammation and dysfunction. The aim of the present study was to investigate the role of long-term oral melatonin administration on ethanol-induced increases in duodenal mucosal permeability and hypermotility.
  
  
  METHODS
  Male Sprague-Dawley rats were administered melatonin in their tap water (0.1 mg mL(-1) or 0.5 mg mL(-1) ) for 2 or 4 weeks. After the treatment period, the rats were anaesthetized with Inactin(®) , and a 30-mm duodenal segment was perfused in situ. The effects on duodenal mucosal paracellular permeability, bicarbonate secretion, fluid flux and motor activity were studied. The expression levels of the tight junction components, zona occludens (ZO)-1, ZO-2, and ZO-3, claudin-2, claudin-3, claudin-4, occludin, and myosin light chain kinase and of the melatonin receptors MT1 and MT2 were assessed using qRT-PCR.
  
  
  RESULTS
  Melatonin administration for 2 weeks significantly reduced the basal paracellular permeability, an effect that was absent after 4 weeks. Perfusing the duodenal segment with 15% ethanol induced marked increases in duodenal paracellular permeability, bicarbonate secretion and motor activity. Melatonin for 2 weeks dose-dependently reduced ethanol-induced increases in permeability and motor activity. Four weeks of melatonin administration reduced the ethanol-induced increases in duodenal motility and bicarbonate secretion but had no effect on the increases in permeability. Two weeks of melatonin administration upregulated the expression of MT1 and MT2 , although both were downregulated after 4 weeks. Melatonin downregulated the expression of ZO-3 and upregulated the expression of claudin-2, even as all other mRNA-levels investigated were unaffected.
  
  
  CONCLUSIONS
  Although further studies are needed, our data demonstrate that melatonin administration markedly improves duodenal barrier functions, suggesting its utility in clinical applications when intestinal barrier functions are compromised.
authors.affiliation: Department of Neuroscience, Division of Gastrointestinal Physiology, Uppsala University, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Sommansson
authors.forename: O
authors.initials: O
authors.lastname: Yamskova
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: O
authors.initials: O
authors.lastname: Nylander
authors.forename: M
authors.initials: M
authors.lastname: Sjöblom
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects*; D004386:Duodenum / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D000431:Ethanol; D008550:Melatonin
keywords: 51Cr-EDTA clearance; duodenal bicarbonate secretion; ethanol; intestinal barrier; intestinal permeability