title: Dimethyl Fumarate Reduces Inflammatory Responses in Experimental Colitis.
abstract: OBJECTIVE
  Fumaric acid esters have been proven to be effective for the systemic treatment of psoriasis and multiple sclerosis. We aimed to develop a new treatment for colitis.
  
  
  METHODS
  We investigated the effect of dimethylfumarate [DMF, 10-30-100mg/kg] on an experimental model of colitis induced by dinitrobenzene sulphuric acid [DNBS]. We also evaluated the therapeutic activity of 7 weeks' treatment with DMF [30mg/kg] on 9-week-old IL-10KO mice that spontaneously develop a T helper-1 [Th1]-dependent chronic enterocolitis after birth, that is fully established at 8-10 weeks of age. The mechanism of this pharmacological potential of DMF [10 μM] was investigated in colonic epithelial cell monolayers [Caco-2] exposed to H2O2. The barrier function was evaluated by the tight junction proteins.
  
  
  RESULTS
  The treatment with DMF significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. DMF [30 and 100mg/kg] also caused a substantial reduction in the degree of colon injury, in the rise in myeloperoxidase [MPO] activity, and in the increase in tumour necrosis factor [TNF]-α expression, as well as in the up-regulation of ICAM-1 caused by DNBS in the colon. Molecular studies demonstrated that DMF impaired NF-κB signalling via reduced p65 nuclear translocalisation. DMF induced a stronger antioxidant response as evidenced by a higher expression of Mn-superoxide dismutase. Moreover, DMF protected human intestinal epithelial cells against H2O2-induced barrier dysfunction, restoring ZO-1 occludin expression, via the HO-1 pathway.
  
  
  CONCLUSIONS
  DMF treatment reduces the degree of colitis caused by DNBS. We propose that DMF treatment may be useful in the treatment of inflammatory bowel disease.
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Casili
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Cordaro
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bruschetta
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy Department of Pharmacological and Physiological Science, St Louis University School of Medicine, St Louis, MO, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy eesposito@unime.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
mesh_terms: D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene; D000069462:Dimethyl Fumarate
keywords: DNBS; Inflammatory bowel diseases; dimethyl fumarate