The phosphodiesterase type 4 inhibitor roflumilast suppresses inflammation to improve diabetic bladder dysfunction rats.

Abstract

To demonstrate that phosphodiesterase type 4 (PDE4) inhibitors could potentially treat diabetic bladder dysfunction (DBD) through modulation of the systemic inflammatory response. In this 6-week study, 60 female Sprague-Dawley rats were divided into three groups: (i) vehicle-treated control rats; (ii) vehicle-treated streptozocin (STZ)-injected rats; and (iii) roflumilast-treated STZ-injected rats. Oral roflumilast (5mg/kg/day) was administered during the last 4 weeks of STZ injection to induce diabetes in the test group. At 6 weeks, a urodynamic study was performed in each group. The expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β in detrusor smooth muscle (DSM) was analyzed using quantitative reverse transcription-polymerase chain reaction and Western blotting. A significant decrease in bodyweight and significant increases in bladder weight and blood glucose level were observed in the diabetic rats and were not ameliorated by roflumilast treatment. Cystometry showed the increased bladder capacity, voiding volume, residual urine volume, and voiding interval in the diabetic rats and the prevention of these changes by roflumilast. These changes were accompanied by significantly enhanced expression of NF-κB, TNF-α, IL-6, and IL-1β in DSM tissue from diabetic rats. Furthermore, roflumilast attenuated the expression of inflammatory factors in DSM tissue. Oral treatment with roflumilast in diabetic rats improves bladder function and inhibits the expression of inflammatory factors in DSM tissue, indicating that PDE4 is a potential therapeutic target for DBD.