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ORIGINAL RESEARCH ARTICLE

Effects of Poly(ADP-Ribose) Polymerase Inhibition in Bladder Damage Caused by Cyclophosphamide in Rats

Ahmet Korkmaz^*, Bülent Kurt, Ibrahim Yildirim, Seref Basal, Turgut Topal^*, Serdar Sadir^* and Sükrü Öter^*,1

^* Department of Physiology, Department of Pathology, and Department of Urology, Gulhane Military Medical Academy, 06018, Ankara, Turkey

To whom requests for reprints should be addressed at ¹ Gulhane Askeri Tip Akademisi, Fizyoloji Anabilim Dali, 06018 – Etlik, Ankara, Turkey. E-mail: oters{at}gata.edu.tr; fizyoter{at}gmail.com

It was previously shown that nitric oxide produced by inducible nitric oxide synthase (iNOS) and peroxynitrite are responsible for cyclophosphamide (CP)-induced cystitis. Since endogenous production of peroxynitrite is known to lead to poly(ADP-ribose) polymerase (PARP) activation, in this study, the aim was to evaluate whether the PARP activation pathway is also included in the pathogenesis of CP-induced bladder ulceration in rats. A total of 48 male albino Wistar rats were divided into 5 groups. Group 1 served as control and was given 2 ml saline; four groups received a single dose of CP (200 mg/kg) with the same time intervals. Group 2 received CP only; Group 3, selective iNOS inhibitor 1400W (20 mg/kg); Group 4, peroxynitrite scavenger ebselen (30 mg/kg); and Group 5, PARP inhibitor 3-aminobenzamide (20 mg/kg). CP injection resulted in severe cystitis with continuous macroscopic hemorrhage, strong edema, inflammation, and ulceration. Moreover, bladder iNOS activation and urine nitrite-nitrate levels were dramatically increased. Histologically, 1400W protected bladder against CP damage and decreased urine nitrite-nitrate levels and bladder iNOS induction. Ebselen has shown similar histologic results with 1400W without changing urinary nitrite-nitrate level and iNOS activity. Furthermore in the 3-aminobenzamide group, beneficial effects had also occurred including decreased ulceration. These results suggest that PARP activation involves pathogenesis of CP-induced bladder ulceration. Furthermore, PARP is not only important for ulceration but also for bladder edema, hemorrhage, and inflammation because of broken uroepithelial cellular integrity.

Key Words: cyclophosphamide • hemorrhagic cystitis • nitric oxide • peroxynitrite • poly(ADP-ribose) polymerase