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Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats.

Research paper by Yao-Chi YC Chuang, Naoki N Yoshimura, Chao-Cheng CC Huang, Moya M Wu, Po-Hui PH Chiang, Michael B MB Chancellor

Indexed on: 03 Jun '08Published on: 03 Jun '08Published in: European Urology



Abstract

Cyclooxygenase 2 (COX-2) elevation and subsequent prostaglandin E(2) (PGE(2)) production play a major role in bladder inflammation and hyperactivity. EP4 receptor, a subtype of PGE(2) receptors, mediates tissue inflammation and hypersensitivity.To investigate the effect of intravesical botulinum toxin A (BoNT-A) on COX-2 and EP4 expression in cyclophosphamide (CYP)-induced cystitis in rats.Experimental (N=40) and control animals (N=20) were injected with CYP (75 mg/kg intraperitoneally) or saline on days 1, 4, and 7. BoNT-A (1 ml, 20 unit/ml) or saline were administered into the bladder and retained for 1 h on day 2.Waking cystometrograms (CMGs) were performed. Bladder and L6 and S1 spinal cord were harvested on day 8.CMG parameters, histology, and COX-2 and EP4 expression by immunostaining or western blotting were measured.CYP induced increased bladder inflammatory reaction, bladder hyperactivity, and COX-2 and EP4 expression in the bladder and spinal cord. The CYP effects were suppressed by BoNT-A treatment. BoNT-A treatment decreased inflammatory reaction (56.5% decrease), COX-2 expression (77.8%, 61.7%, and 54.8% decrease for bladder, L6, and S1 spinal cord, respectively), EP4 expression (56.8%, 26.9%, and 84.2% decrease for bladder, L6, and S1 spinal cord, respectively), and suppressed bladder hyperactivity (intercontraction interval, 107% increase and contraction amplitude, 43% decrease).CYP injection activated COX2 and EP4 expression in the bladder and spinal cord and induced bladder inflammation and hyperactivity, which effects were suppressed by BoNT-A treatment. These findings suggest a potential benefit of EP4-targeted pharmacotherapy and BoNT-A treatment for bladder inflammatory conditions.