Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa
Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa
复制标题
DOI：
10.1016/j.freeradbiomed.2008.06.020
复制
发表时间：
2008-09-15
影响因子：
7.4
通讯作者：
Campochiaro, Peter A.
中科院分区：
文献类型：
--
作者：
Komeima, Keiichi;Usui, Shinichi;Campochiaro, Peter A.
视网膜色素变性（RP）是一组疾病，其中许多不同的突变导致视杆细胞死亡，然后由于进行性氧化损伤而逐渐导致视锥细胞死亡。在这项研究中，我们已经表明，过氧亚硝酸盐诱导的亚硝化损伤也发生。在rd 1小鼠模型的RP，有增加染色的S-亚硝基半胱氨酸和硝基酪氨酸蛋白加合物，产生的过氧亚硝酸盐。过氧亚硝酸盐由一氧化氮（NO）和超氧自由基产生。视杆细胞变性后，注射氢乙啶导致rd 1小鼠视网膜中出现强烈荧光，表明超氧自由基水平较高，而这一点被夹竹桃苷减少，硝基酪氨酸染色也是如此，表明NADP（H）氧化酶的过度作用至少是部分原因。用一氧化氮合酶（NOS）抑制剂的混合物治疗rd 1小鼠显著降低了S-亚硝基半胱氨酸和硝基酪氨酸染色，并显着增加视锥细胞的存活，表明NO衍生的过氧亚硝酸盐有助于视锥细胞死亡。7-硝基吲唑，一种相对特异性的神经元NOS抑制剂，治疗也显着减少视锥细胞死亡，但氨基胍，一种相对特异性的诱导型NOS抑制剂，没有。这些数据表明，神经元NOS产生的NO加剧了RP视锥细胞的氧化损伤，应考虑联合治疗，以减少NO和氧化应激。(C)2008年爱思唯尔公司All rights reserved.
Retinitis pigmentosa (RP) is a group of diseases in which many different Mutations cause rod photoreceptor cells to die and then gradually cone photoreceptors die due to progressive oxidative damage. In this study, we have shown that peroxynitrite-induced nitrosative damage also occurs. In the rd1 mouse model of RP, there was increased staining for S-nitrosocysteine and nitrotyrosine protein adducts that are generated by peroxynitrite. Peroxynitrite is generated from nitric oxide (NO) and superoxide radicals. After degeneration of rods, injection of hydroethidine resulted in strong fluorescence in the retina of rd1 mice, indicating high levels of superoxide radicals, and this was reduced, as was nitrotyrosine staining, by apocynin, suggesting that overaction of NADP(H) oxidase is at least partially responsible. Treatment of rd1 mice with a mixture of nitric oxide synthase (NOS) inhibitors markedly reduced S-nitrosocysteine and nitrotyrosine staining and significantly increased cone survival, indicating that NO-derived peroxynitrite contributes to cone cell death. Treatment with 7-nitroindazole, a relatively specific inhibitor of neuronal NOS, also significantly reduced cone cell death, but aminoguanidine, a relatively specific inhibitor of inducible NOS, did not. These data suggest that NO generated by neuronal NOS exacerbates oxidative damage to cones in RP and that combined therapy to reduce NO and oxidative stress should be considered. (C) 2008 Elsevier Inc. All rights reserved.