Abstract
Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via off-label routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mg·kg-1·day-1), oral roflumilast (5 mg·kg-1·day-1), or rectal roflumilast (5 mg·kg-1·day-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-α. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-α, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.
Highlights
The prevalence of Crohn’s disease (CD), a predominant type of inflammatory bowel disease (IBD), has been increasing over the last decades
We hypothesized that treatment with rectal roflumilast will significantly improve Trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis in rats
The sulfasalazine group showed marked improvement, the oral roflumilast group showed moderate to marked improvement, and the rectal roflumilast group showed mild improvement (Figure 1C)
Summary
The prevalence of Crohn’s disease (CD), a predominant type of inflammatory bowel disease (IBD), has been increasing over the last decades. CD is a chronic, idiopathic, immunologically mediated disease that is triggered in a genetically predisposed person by multiple environmental factors [1]. CD occurs as a patchy granuloma affecting any part of the gastrointestinal tract, especially the ileum and first part of the colon. It involves the entire bowel wall and manifests as abdominal masses and perianal lesions. It is necessary to search for new medications for CD and, to be relevant to human CD, the animal model should be already established, chronic, and immune-mediated [3]. Trinitrobenzene sulfonic acid (TNBS) induces an experimental model of colitis with a T helper 1 (Th1) immune pattern that is similar to human CD, but with certain limitations [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
