Repurposing dimethyl fumarate for gastric ulcer and ulcerative colitis: Evidence of local efficacy without systemic side effect

Abstract

Ulcerative colitis and gastric ulcer are ulcers of gastrointestinal track, especially associated with elevated oxidative stress and inflammation. Dimethyl fumarate (DMF) is used for the treatment of multiple sclerosis and psoriasis and is considered useful in a variety of conditions associated with inflammation. We have investigated the effect of oral DMF (1, 10, 25, 50, 100, 200 mg/kg) in ethanol-induced gastric ulcers in rats. The effect of oral (15, 30, and 60 mg/kg) and intracecal (15 mg/kg) DMF was also investigated in dextran sulfate sodium (DSS)-induced colitis in mice. Treatment of DMF by oral route prevented the development of ethanol-induced gastric ulcers by decreasing oxidative stress in a dose-related manner. Oral and intracecal administration of DMF attenuated body weight loss, increase in disease activity score, colon length shortening, colon weight loss, inflammation and fibrosis, and decreased myeloperoxidase activity. Oral and intracecal DMF prevented a decrease in hemoglobin and suppressed oxidative stress, and also decreased MCP-1, IL-1ß, and IL-6 levels in the inflamed colon. Unlike oral DMF, intracecal DMF treatment did not reduce spleen weight. The effect of intracecal DMF was similar to the highest tested dose of oral DMF (60 mg/kg). These results demonstrated that intracecal DMF suppresses inflammation and oxidative stress in ethanol and DSS-induced colitis without alteration of spleen weight. This suggests that the localized DMF administration could be beneficial approach of treating gastrointestinal ulcers.