Giovanna Casili1, Marika Cordaro1, Daniela Impellizzeri1, Giuseppe Bruschetta1, Irene Paterniti1, Salvatore Cuzzocrea2, Emanuela Esposito3. 1. Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy. 2. 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. 3. Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Messina, Italy eesposito@unime.it.
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.
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: Duvyanshu Dubey; Bernd C Kieseier; Hans P Hartung; Bernhard Hemmer; Clemens Warnke; Til Menge; William A Miller-Little; Olaf Stuve Journal: Expert Rev Neurother Date: 2015-04 Impact factor: 4.618
Authors: Hester Eppinga; H Bing Thio; Marco W J Schreurs; Blerdi Blakaj; Ruena I Tahitu; Sergey R Konstantinov; Maikel P Peppelenbosch; Gwenny M Fuhler Journal: PLoS One Date: 2017-05-09 Impact factor: 3.240