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


METHODS
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.


METHODS
Waking cystometrograms (CMGs) were performed. Bladder and L6 and S1 spinal cord were harvested on day 8.


METHODS
CMG parameters, histology, and COX-2 and EP4 expression by immunostaining or western blotting were measured.


CONCLUSIONS
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.
Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Chuang82@ms26.hinet.net
Yao-Chi
YC
Chuang
Naoki
N
Yoshimura
Chao-Cheng
CC
Huang
Moya
M
Wu
Po-Hui
PH
Chiang
Michael B
MB
Chancellor
D000283:Administration, Intravesical; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000150:complications*; D005260:Female; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013116:Spinal Cord / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology
D052246:Cyclooxygenase 2 Inhibitors; D009498:Neurotoxins; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003520:Cyclophosphamide; D019274:Botulinum Toxins, Type A