Dimethyl Fumarate Reduces Inflammatory Responses in Experimental Colitis.

Abstract

BACKGROUND AND AIMS:

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: Giovanna Casili, Marika Cordaro, Daniela Impellizzeri, Giuseppe Bruschetta, Irene Paterniti, Salvatore Cuzzocrea, Emanuela Esposito
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 10 Issue 4 Pg. 472-83 (Apr 2016) ISSN: 1876-4479 [Electronic] England
• PMID: 26690241 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• P-Selectin
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Interleukin-10
• 2,4-dinitrofluorobenzene sulfonic acid
• Dinitrofluorobenzene
• Dimethyl Fumarate

Topics

• Animals
• Caco-2 Cells (drug effects)
• Colitis (chemically induced, drug therapy)
• Dimethyl Fumarate (therapeutic use)
• Dinitrofluorobenzene (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Humans
• Intercellular Adhesion Molecule-1 (physiology)
• Interleukin-10 (physiology)
• Male
• Mice
• Mice, Knockout
• P-Selectin (physiology)
• Tumor Necrosis Factor-alpha (physiology)