Roflumilast, type 4 phosphodiesterase inhibitor, attenuates inflammation in rats with ulcerative colitis via down-regulation of iNOS and elevation of cAMP

Background: Roflumilast (Rof), a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be an effective agent in inflammatory diseases and marketed for chronic obstructive pulmonary disease. Objective: This study was conducted to examine the potential anti-inflammatory effects of Rof in dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in rats and to investigate the molecular mechanisms underlying these effects. Methods: Forty male Wistar rats were divided into four groups: normal control, colitis group (rats received 5% DSS in their drinking water continuously for 7 days), Rof group, and sulfasalazine (SLZ) group. The Rof (5 mg/kg) and SLZ (500 mg/kg) groups underwent pretreatment with DSS one week ahead of DSS challenge and parallel with DSS. Colitis was determined by assessing colon length, weight loss, histologic colon score, quantifying the concentration of tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO), cyclic adenosine mono-phosphate (cAMP), myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) gene expression in colon tissue. Results: Rof attenuated the severity of colitis as evidenced by increased colon length, prevention of body weight loss, and improved colon histologic score compared to DSS group. Rof also suppressed the inflammatory response induced in DSS colitis group by decreasing colon concentration of TNF-alpha, NO and MPO activity and down-regulation of iNOS gene expression. The level of cAMP was increased by Rof compared to DSS group. The obtained results of Rof were comparable to those exerted by SLZ. Conclusion: These findings revealed the beneficial effects of Rof in alleviating inflammation in DSS colitis.