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  • Title: Poly(Adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury.
    Author: Kendirci M, Zsengellér Z, Bivalacqua TJ, Gur S, Usta MF, Chen M, Szabó C, Hellstrom WJ.
    Journal: J Urol; 2005 Nov; 174(5):2054-9. PubMed ID: 16217393.
    Abstract:
    PURPOSE: 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. MATERIALS AND 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.
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