Centro de Investigación Biomédica, Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
J Neurosci Res. 2009 Oct;87(13):3002-10. doi: 10.1002/jnr.22123.
Melatonin prevents mitochondrial failure in models of sepsis through its ability to inhibit the expression and activity of both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases. Because Parkinson's disease (PD), like sepsis, is associated with iNOS induction, we assessed the existence of changes in iNOS/i-mtNOS and their relation with mitochondrial dysfunction in the MPTP model of PD, which also displays increased iNOS expression. We also evaluated the role of melatonin (aMT) and its brain metabolite, N(1)-acetyl-5-methoxykynuramine (AMK), in preventing i-mtNOS induction and mitochondrial failure in this model of PD. Mitochondria from substantia nigra (SN) and, to a lesser extent, from striatum (ST) showed a significant increase in i-mtNOS activity, nitrite levels, oxidative stress, and complex I inhibition after MPTP treatment. MPTP-induced i-mtNOS was probably related to mitochondrial failure, because its prevention by aMT and AMK reduced oxidative/nitrosative stress and restored complex I activity. These findings represent the first experimental evidence of a potential role for i-mtNOS in the mitochondrial failure of PD and support a novel mechanism in the neuroprotective effects of aMT and AMK.
褪黑素通过抑制细胞质（iNOS）和线粒体（i-mtNOS）诱导型一氧化氮合酶的表达和活性来防止脓毒症模型中的线粒体衰竭。由于帕金森病（PD）与 iNOS 诱导有关，我们评估了在 PD 的 MPTP 模型中 iNOS/i-mtNOS 的变化及其与线粒体功能障碍的关系，该模型也显示 iNOS 表达增加。我们还评估了褪黑素（aMT）及其脑代谢物 N（1）-乙酰-5-甲氧基色氨酸（AMK）在预防 PD 模型中 i-mtNOS 诱导和线粒体衰竭中的作用。MPTP 处理后，黑质（SN）和（程度较小）纹状体（ST）的线粒体中 i-mtNOS 活性、亚硝酸盐水平、氧化应激和复合物 I 抑制显著增加。MPTP 诱导的 i-mtNOS 可能与线粒体衰竭有关，因为 aMT 和 AMK 的预防可降低氧化/硝化应激并恢复复合物 I 活性。这些发现代表了 i-mtNOS 在 PD 线粒体衰竭中潜在作用的第一个实验证据，并支持 aMT 和 AMK 的神经保护作用的新机制。
