Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: Evidence for a protective role of acetylcarnitine
Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: Evidence for a protective role of acetylcarnitine
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DOI：
10.1023/a:1024984013069
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发表时间：
2003-09-01
影响因子：
4.4
通讯作者：
Stella, AMG
中科院分区：
文献类型：
--
作者：
Calabrese, V;Scapagnini, G;Stella, AMG
最近的研究表明，NO 及其活性衍生物过氧亚硝酸盐与多发性硬化症 (MS) 的发病机制有关。死于多发性硬化症的患者表现出星形细胞诱导型一氧化氮合酶活性增加，以及 iNOS mRNA 水平增加。过氧亚硝酸盐是一种强氧化剂，能够损害靶组织，尤其是大脑，而众所周知，大脑的抗氧化缓冲能力较差。实验性过敏性脑脊髓炎 (EAE) 动物和 MS 患者的中枢神经系统 (CNS) 中诱导型一氧化氮合酶上调。我们最近在活动性多发性硬化症患者中证明，NOS 活性显着增加，与脑脊液 (CSF) 中蛋白质硝化增加相关。乙酰肉碱被提议作为多种神经退行性疾病的治疗剂。因此，在本研究中，多发性硬化症患者接受乙酰肉碱治疗 6 个月，并与未经治疗的多发性硬化症受试者或非炎症性神经系统疾病患者（作为对照）进行比较。蛋白质印迹分析显示，多发性硬化症患者的亚硝化应激增加与还原型谷胱甘肽 (GSH) 的显着减少相关。还观察到氧化谷胱甘肽 (GSSG) 和亚硝基硫醇水平升高。有趣的是，用乙酰肉碱治疗多发性硬化症患者会导致脑脊液中NO反应性代谢物和蛋白质硝化水平降低，以及GSH含量和GSH/GSSG比值升高。我们的数据支持这样的假设：亚硝化应激是受 MS 影响的中枢神经系统产生 NO 的主要后果，并暗示乙酰肉碱在保护大脑免受亚硝化应激中可能发挥重要作用，这可能是 MS 发病机制的基础。
Recent studies suggest that NO and its reactive derivative peroxynitrite are implicated in the pathogenesis of multiple sclerosis (MS). Patients dying with MS demonstrate increased astrocytic inducible nitric oxide synthase activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong oxidant capable of damaging target tissues, particularly the brain, which is known to be endowed with poor antioxidant buffering capacity. Inducible nitric oxide synthase is upregulated in the central nervous system (CNS) of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. We have recently demonstrated in patients with active MS a significant increase of NOS activity associated with increased nitration of proteins in the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, in the present study, MS patients were treated for 6 months with acetylcarnitine and compared with untreated MS subjects or with patients noninflammatory neurological conditions, taken as controls. Western blot analysis showed in MS patients increased nitrosative stress associated with a significant decrease of reduced glutathione (GSH). Increased levels of oxidized glutathione (GSSG) and nitrosothiols were also observed. Interestingly, treatment of MS patients with acetylcarnitine resulted in decreased CSF levels of NO reactive metabolites and protein nitration, as well as increased content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that nitrosative stress is a major consequence of NO produced in MS-affected CNS and implicate a possible important role for acetylcarnitine in protecting brain against nitrosative stress, which may underlie the pathogenesis of MS.