Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.

中文翻译：

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用烟酰胺核糖靶向sirtuin活性可以减少GWI小鼠模型的神经炎症。

海湾战争疾病（GWI）影响1991年海湾战争（GW）中的30％退伍军人，他们的症状反映了持续的线粒体功能障碍。GWI动物模型中的脑线粒体生物能功能障碍与星形胶质细胞活化和神经炎症反应相对应。在GW退伍军人（n = 43）的一项初步研究中，我们观察到与健康的GW退伍军人相比，GWI退伍军人血液中的烟酰胺腺嘌呤二核苷酸（NAD）和sirtuin 1（Sirt1）蛋白水平降低。由于烟酰胺核糖苷（NR）介导的Sirt1靶向可改善线粒体功能，因此我们测试了NR是否可以在GWI小鼠模型中恢复大脑生物能并减少神经炎症。我们向GWI和对照小鼠（n = 27）每天喂食补充了NR的小鼠饮食，每天100μg/ kg。治疗期间 使用强迫游泳测试（FST）对小鼠的疲劳类型行为进行评估，然后对安乐死进行生化和免疫组织化学分析。与对照小鼠相比，GWI小鼠的疲劳类型行为升高，与未治疗的GWI小鼠相比，用NR处理的GWI小鼠疲劳类型行为降低。在未经治疗的GWI小鼠中血浆NAD和脑Sirt1的水平较低，而经NR处理的GWI小鼠具有较高的水平，与对照小鼠相似。NR处理的GWI小鼠的大脑中核因子κB（NFκB）p65亚基和过氧化物酶体增殖物激活的受体γ共激活因子1-α（PGC-1α）的脱乙酰作用增加。这与GWI小鼠大脑中促炎性细胞因子和脂质过氧化作用的减少以及线粒体生物能学标志物的增加相对应。这些发现表明，靶向NR介导的Sirt1激活可恢复大脑生物能，并减少GWI小鼠的炎症。有必要对GWI中的NR进行进一步评估，以确定其在治疗GWI中的潜在功效。