Intravesical Botulinum Toxin A Administration Inhibits COX-2 and EP4 Expression and Suppresses Bladder Hyperactivity in Cyclophosphamide-Induced Cystitis in Rats
Intravesical Botulinum Toxin A Administration Inhibits COX-2 and EP4 Expression and Suppresses Bladder Hyperactivity in Cyclophosphamide-Induced Cystitis in Rats
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DOI：
10.1016/j.eururo.2008.05.007
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发表时间：
2009-07-01
期刊：
影响因子：
23.4
通讯作者：
Chancellor, Michael B.
中科院分区：
文献类型：
--
作者：
Chuang, Yao-Chi;Yoshimura, Naoki;Chancellor, Michael B.
背景资料：环氧合酶2（考克斯-2）升高和随后的前列腺素E（2）（PGE（2））产生在膀胱炎症和活动过度中起主要作用。EP 4受体是前列腺素E（2）受体的一个亚型，介导组织炎症和超敏反应。目的：研究膀胱内注射肉毒杆菌毒素A（BoNT-A）对环磷酰胺（cyclophosphamide，CTX）诱导的大鼠膀胱炎中考克斯-2和EP 4表达的影响。在第1、4天，实验动物（N = 40）和对照动物（N = 20）注射了地塞米松（75 mg/kg，腹膜内）或生理盐水。和7.第2天将BoNT-A（1 ml，20单位/ml）或生理盐水注入膀胱并保留1h。干预：进行唤醒膀胱测压（CMG）。方法：采用免疫组化和Western blotting方法检测大鼠膀胱、脊髓组织中考克斯-2和EP 4的表达，并与正常对照组比较。结果：膀胱炎性反应、膀胱活动度、考克斯-2和EP 4的表达均增加。BoNT-A处理抑制了这种抑制作用。BoNT-A治疗降低了炎症反应（降低56.5%），考克斯-2表达（膀胱、L 6和S1脊髓分别减少77.8%、61.7%和54.8%），EP 4表达（膀胱、L 6和S1脊髓分别减少56.8%、26.9%和84.2%），并抑制膀胱过度活动结论：肉毒毒素注射液可激活膀胱和脊髓中COX 2和EP 4的表达，诱导膀胱炎症和活动过度，而肉毒毒素A可抑制这种作用。这些发现表明，EP 4靶向药物治疗和BoNT-A治疗膀胱炎性疾病的潜在益处。(C)2008年欧洲泌尿外科协会。Elsevier B. V.出版，保留所有权利。
Background: 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.Objective: To investigate the effect of intravesical botulinum toxin A (BoNT-A) on COX-2 and EP4 expression in cyclophosphamide (CYP)-induced cystitis in rats.Design, setting, and participants: 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.Intervention: Waking cystometrograms (CMGs) were performed. Bladder and L6 and S1 spinal cord were harvested on day 8.Measurements: CMG parameters, histology, and COX-2 and EP4 expression by immunostaining or western blotting were measured.Results and limitations: 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).Conclusions: 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. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.