Poly(adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury
Poly(adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury
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DOI：
10.1097/01.ju.0000176484.35636.e5
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发表时间：
2005-11-01
影响因子：
6.6
通讯作者：
Hellstrom, WJG
中科院分区：
文献类型：
--
作者：
Kendirci, M;Zsengellér, Z;Hellstrom, WJG
目的：在大鼠双侧海绵状神经挤压损伤(BCNCI)模型上，探讨聚二磷酸腺苷核糖聚合酶(PARP)激活在勃起功能障碍发生中的作用及PARP抑制剂INO-1001的治疗作用。材料与方法：SD大鼠分为假手术组、BCNCI+Vehicle组和BCNCI+PARP抑制剂INO-1001组。手术干预1周后，各组动物均接受体内海绵体神经刺激。免疫组织化学方法检测PAR活性、硝基酪氨酸和诱导型一氧化氮合酶活性，高效液相色谱法测定血清INO-1001水平。分析阴茎组织中丙二醛和髓过氧化物酶的水平。结果：对神经源性勃起反应进行评估。BCNCI+Vehicle组大鼠的平均海绵体内压、颅内压/血压比和总颅内压显著降低。这些值在假手术组和PARP抑制剂治疗组之间没有统计学差异。治疗组PAR染色明显减少。对BCNCI的反应是，丙二醛组织水平显著增加，但髓过氧化物酶水平没有增加，这一点在PARP抑制剂治疗后没有变化。治疗组酪氨酸硝化反应明显增加。治疗组大鼠阴茎组织中未见一氧化氮合酶表达上调和酪氨酸硝化增加。结论：BCNCI模型大鼠阴茎组织中PARP活性升高，导致严重的勃起功能障碍。使用PARP抑制剂INO-1001治疗可降低亚硝化应激程度，防止PARP激活，并提供显著的海绵体神经保护，进而保留勃起功能。
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.