Metals, oxidative stress and neurodegenerative disorders
Metals, oxidative stress and neurodegenerative disorders
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DOI：
10.1007/s11010-010-0563-x
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发表时间：
2010-12-01
影响因子：
4.3
通讯作者：
Valko, Marian
中科院分区：
文献类型：
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作者：
Jomova, Klaudia;Vondrakova, Dagmar;Valko, Marian
神经退行性疾病，阿尔茨海默病（AD）和帕金森病（PD），是与年龄相关的疾病，其特征在于异常形式的特定蛋白质在脑中的沉积。AD的特征在于脑中存在细胞外淀粉样蛋白斑块和神经元内神经元缠结。淀粉样斑块的生化分析揭示，主要成分是被称为淀粉样β蛋白（A β）的39-42个残基肽的纤维状聚集体。帕金森病与黑质多巴胺能神经元的变性有关。PD的病理学标志之一是存在称为Lewy小体的细胞内包涵体，其由称为α-突触核蛋白的突触前可溶性蛋白的聚集体组成。有各种因素影响的病理沉积，并在一般情况下，神经系统疾病的神经元死亡的原因似乎是多因素的。然而，很明显，神经系统疾病的潜在因素是增加的氧化应激，这一发现证实了蛋白质侧链直接被活性氧（ROS）或活性氮（RNS）修饰，或间接被脂质过氧化产物修饰。AD脑中氧化应激水平的增加通过铁（Fe）和铜（Cu）的脑含量增加来反映，铁（Fe）和铜（Cu）都能够刺激自由基形成（例如，G.羟基自由基通过芬顿反应），增加AD脑中的蛋白质和DNA氧化，增强脂质过氧化，降低细胞色素c氧化酶和晚期糖基化终产物（AGEs）、羰基、丙二醛（MDA）、过氧亚硝酸盐和血红素加氧酶-1（HO-1）的水平。AGEs主要通过与晚期糖基化终产物受体（RAGE）相互作用，进一步激活信号通路，诱导促炎细胞因子如白细胞介素-6（IL-6）的形成。酪氨酸残基的共轭芳环是自由基攻击的靶标，并且在AD脑中也报道了二酪氨酸和3-硝基酪氨酸的积累。与PD相关的氧化应激得到了尸检研究和显示黑质丘脑部氧化应激水平增加的研究的支持，从而证明了氧化应激诱导黑质细胞变性的能力。脂质过氧化的标志物包括4-羟基-反式-2-壬烯醛（HNE）、4-氧代-反式-2-壬烯醛（4-ONE）、丙烯醛和4-氧代-反式-2-己烯醛，所有这些都是公认的神经毒性物质。此外，其他重要因素，包括炎症，一氧化氮（NO中心点）的毒性作用，蛋白质清除的缺陷和线粒体功能障碍都有助于PD的病因。有人认为，几种单独的抗氧化剂或它们的组合可以保护神经，降低AD的风险或减缓其进展。本文就氧化还原金属铁、铜和非氧化还原金属锌在AD和PD的氧化应激相关病因学中的作用进行综述。注意力集中在金属诱导的自由基形成和抗氧化剂[谷胱甘肽（GSH），维生素C（抗坏血酸）]，维生素E（α-生育酚），硫辛酸，类黄酮[儿茶素，表没食子儿茶素没食子酸酯（EGCG）]和姜黄素的保护作用。另一个在AD假设主题进行了讨论。
The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-beta protein (A beta). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called alpha-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation. The increased level of oxidative stress in AD brain is reflected by the increased brain content of iron (Fe) and copper (Cu) both capable of stimulating free radical formation (e. g. hydroxyl radicals via Fenton reaction), increased protein and DNA oxidation in the AD brain, enhanced lipid peroxidation, decreased level of cytochrome c oxidase and advanced glycation end products (AGEs), carbonyls, malondialdehyde (MDA), peroxynitrite, and heme oxygenase-1 (HO-1). AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs), further activate signaling pathways, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6). The conjugated aromatic ring of tyrosine residues is a target for free-radical attack, and accumulation of dityrosine and 3-nitrotyrosine has also been reported in AD brain. The oxidative stress linked with PD is supported by both postmortem studies and by studies showing the increased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus the capacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, other important factors, involving inflammation, toxic action of nitric oxide (NO center dot), defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD. It has been suggested that several individual antioxidants or their combinations can be neuroprotective and decrease the risk of AD or slow its progression. The aim of this review is to discuss the role of redox metals Fe and Cu and non-redox metal zinc (Zn) in oxidative stress-related etiology of AD and PD. Attention is focused on the metal-induced formation of free radicals and the protective role of antioxidants [glutathione (GSH), vitamin C (ascorbic acid)], vitamin E (alpha-Tocopherol), lipoic acid, flavonoids [catechins, epigallocatechin gallate (EGCG)], and curcumin. An alternate hypothesis topic in AD is also discussed.