Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage
Melatonin influences NO/NOS pathway and reduces oxidative and nitrosative stress in a model of hypoxic-ischemic brain damage
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DOI：
10.1016/j.niox.2016.12.001
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发表时间：
2017-01-30
影响因子：
3.9
通讯作者：
Angeles Peinado, Maria
中科院分区：
文献类型：
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作者：
Blanco, Santos;Hernandez, Raquel;Angeles Peinado, Maria
在这项工作中，我们使用大鼠缺血和低压缺氧（IH）联合模型，评估抗氧化褪黑素与脑一氧化氮/一氧化氮合酶（NO/NOS）系统之间的关系，试图确定褪黑素是否通过平衡这一关键途径发挥其抗氧化保护作用，这一关键途径高度参与这些病理下的脑氧化和亚硝化损伤。IH模型的应用增加了三种一氧化氮合酶（NOS）异构体的表达，以及大脑皮层氮氧化物（NOx）水平和硝基酪氨酸（n-Tyr）的影响。然而，在IH前给药褪黑激素使nNOS表达反应更早、更强，但减少iNOS和n-Tyr表达，而eNOS和NOx保持不变。这些结果证实了尼古丁腺嘌呤二核苷酸磷酸二磷酸（NADPH-d）染色，作为原位NOS活性的指示。此外，用硫代巴比妥酸活性物质（TBARS）评估，先前用褪黑素治疗的大鼠表现出氧化影响的减少。最后，IH还增强了胶质原纤维酸性蛋白（GFAP）的表达，降低了缺氧诱导因子- α (HIF-1 α)，但未改变核因子κ B (nf - κ B)；同时，在应用IH模型后，褪黑激素对这些模式都没有显著影响。抗氧化褪黑素作用于IH损伤后的NO/NOS系统，平衡NO的释放，减少过氧亚硝酸盐的形成，防止亚硝化/氧化损伤。此外，本文还对一些有争议的分子（如NO）的经典作用提出了质疑，这些分子在缺氧神经元的最终命运中起着重要作用。我们得出结论，褪黑激素在缺血级联的第一步保护大脑免受缺氧/缺血性损伤，影响NO/NOS通路并减少氧化和亚硝化应激。(C) 2016 Elsevier Inc.版权所有。
In this work, using a rat model combining ischemia and hypobaric hypoxia (IH), we evaluate the relationships between the antioxidant melatonin and the cerebral nitric oxide/nitric oxide synthase (NO/NOS) system seeking to ascertain whether melatonin exerts its antioxidant protective action by balancing this key pathway, which is highly involved in the cerebral oxidative and nitrosative damage underlying these pathologies.The application of the IH model increases the expression of the three nitric oxide synthase (NOS) isoforms, as well as nitrogen oxide (NOx) levels and nitrotyrosine (n-Tyr) impacts on the cerebral cortex. However, melatonin administration before IH makes nNOS expression response earlier and stronger, but diminishes iNOS and n-Tyr expression, while both eNOS and NOx remain unchanged. These results were corroborated by nicotine adenine dinucleotide phosphate diaphorase (NADPH-d) staining, as indicative of in situ NOS activity. In addition, the rats previously treated with melatonin exhibited a reduction in the oxidative impact evaluated by thiobarbituric acid reactive substances (TBARS). Finally, IH also intensified glial fibrillary acidic protein (GFAP) expression, reduced hypoxia-inducible factor-lalpha (HIF-1 alpha), but did not change nuclear factor kappa B (NF-kappa B); meanwhile, melatonin did not significantly affect any of these patterns after the application of the IH model.The antioxidant melatonin acts on the NO/NOS system after IH injury balancing the release of NO, reducing peroxynitrite formation and protecting from nitrosative/oxidative damage. In addition, this paper raises questions concerning the classical role of some controversial molecules such as NO, which are of great consequence in the final fate of hypoxic neurons.We conclude that melatonin protects the brain from hypoxic/ischemic-derived damage in the first steps of the ischemic cascade, influencing the NO/NOS pathway and reducing oxidative and nitrosative stress. (C) 2016 Elsevier Inc. All rights reserved.