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, 10-30-100 mg/kg) on an experimental model of colitis induced by DNBS. We also evaluated the therapeutic activity of 7 weeks treatment of DMF (30 mg/kg) on 9-week-old IL-10KO mice that spontaneously develop a Th1-dependent chronic enterocolitis after birth that is fully established at 8-10 weeks of age. The mechanism of this pharmacological potential of DMF (10μM) 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 hemorrhagic diarrhea and weight loss caused by administration of DNBS. DMF (30 and 100 mg/kg) also caused a substantial reduction in the degree of colon injury, in the rise in MPO activity, in the increase in 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 signaling via reduced p65 nuclear translocalization. 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.

Fumaric acid esters and inflammatory responses

BIUNDO, FLAVIA
2017-01-23

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, 10-30-100 mg/kg) on an experimental model of colitis induced by DNBS. We also evaluated the therapeutic activity of 7 weeks treatment of DMF (30 mg/kg) on 9-week-old IL-10KO mice that spontaneously develop a Th1-dependent chronic enterocolitis after birth that is fully established at 8-10 weeks of age. The mechanism of this pharmacological potential of DMF (10μM) 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 hemorrhagic diarrhea and weight loss caused by administration of DNBS. DMF (30 and 100 mg/kg) also caused a substantial reduction in the degree of colon injury, in the rise in MPO activity, in the increase in 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 signaling via reduced p65 nuclear translocalization. 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11570/3103430
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