Poly(Adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury.
OBJECTIVE
We investigated the involvement of poly(adenosine diphosphate-ribose) (PAR) polymerase (PARP) activation in the development of erectile dysfunction and the therapeutic benefit of the potent PARP inhibitor INO-1001 (Inotek Pharmaceuticals Corp., Beverly, Massachusetts) in a bilateral cavernous nerve crush injury (BCNCI) model in rats.


METHODS
Sprague-Dawley rats were divided into 3 groups, namely sham treated, BCNCI plus vehicle and BCNCI plus the PARP inhibitor INO-1001. One week after surgical intervention all groups underwent in vivo cavernous nerve stimulation. PAR activation, nitrotyrosine and inducible nitric oxide synthase were evaluated by immunohistochemistry and serum levels of INO-1001 were measured by high performance liquid chromatography. Penile tissues were analyzed for levels of malondialdehyde and myeloperoxidase. Data sets were statistically compared in all groups.


RESULTS
Neurogenic mediated erectile responses were evaluated. Mean intracavernous pressure (ICP), the ICP-to-blood-pressure ratio and total ICP were significantly decreased in BCNCI plus vehicle rats. These values were not statistically different between the sham and PARP inhibitor treated groups. There was a marked decrease in PAR staining in the treatment group. There was a substantial increase in malondialdehyde tissue levels but not myeloperoxidase in response to BCNCI, which was unchanged with PARP inhibitor treatment. There was a marked increase in tyrosine nitration in the treatment group. Up-regulation of nitric oxide synthase and increased tyrosine nitration were not observed in the penile tissues of the treatment group.


CONCLUSIONS
These data demonstrate that BCNCI in a rat model causes increased PARP activation, resulting in severe erectile dysfunction. Treatment with the PARP inhibitor INO-1001 decreases the degree of nitrosative stress, prevents PARP activation and provides significant cavernous neuroprotection, which in turn preserves erectile function.
Kendirci
Muammer
M
Department of Urology, School of Medicine, Tulane University, New Orleans, Louisiana, USA.
Zsengellér
Zsuzsanna
Z
Bivalacqua
Trinity J
TJ
Gur
Serap
S
Usta
Mustafa F
MF
Chen
Min
M
Szabó
Csaba
C
Hellstrom
Wayne J G
WJ
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D010413:Penis / Q000293:injuries / Q000294:innervation; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects* / Q000378:metabolism; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity
C491685:INO 1001; D007211:Indoles; D000246:Adenosine Diphosphate Ribose; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D011065:Poly(ADP-ribose) Polymerases