title: Effects of poly(ADP-ribose) polymerase inhibition in bladder damage caused by cyclophosphamide in rats.
abstract: 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.
authors.affiliation: Department of Physiology, Gulhane Military Medical Academy, 06018, Ankara, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Korkmaz
authors.forename: Bülent
authors.initials: B
authors.lastname: Kurt
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Yildirim
authors.forename: Seref
authors.initials: S
authors.lastname: Basal
authors.forename: Turgut
authors.initials: T
authors.lastname: Topal
authors.forename: Serdar
authors.initials: S
authors.lastname: Sadir
authors.forename: Sükrü
authors.initials: S
authors.lastname: Oter
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D015538:Nitrosation; D009929:Organ Size / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D001745:Urinary Bladder Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003520:Cyclophosphamide; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases