EVALUATION OF THE SAFETY, TOLERABILITY AND IMPACT ON BIOMARKERS OF ANTI-OXIDANT

抗氧化剂的安全性、耐受性和对生物标志物的影响的评估

• 批准号: 7606656
• 负责人: RUTH MULNARD MCCARGAR
• 金额: $ 0.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606656
• 关键词: Acetylcholinesterase Inhibitors; Activities of Daily Living; Adverse event; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antioxidants; Apoptosis; Ascorbic Acid; Astrocytes; Biochemical Markers; Biological Markers; Brain; Canis familiaris; Cerebrospinal Fluid; Cerebrum; Cessation of life; Clinical; Clinical Trials; Coenzyme Q10; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Controlled Clinical Trials; County; Cultured Cells; Cytosol; DNA; DNA Damage; Data; Degenerative Disorder; Dementia; Deposition; Diffuse; Discrimination Learning; Disease; Dose; Elderly; Epidemiologic Studies; Etiology; Exposure to; Facilities and Administrative Costs; Funding; Grant; Homeostasis; Individual; Institution; Institutionalization; Isoprostanes; Lead; Life Expectancy; Link; Lipid Peroxidation; Lipids; Lymphocyte; Measurement; Mediator of activation protein; Memantine; Membrane; Memory Loss; Microglia; Mitochondria; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurotransmitters; Nitrates; Oxidative Stress; Participant; Patients; Personal Communication; Personal Satisfaction; Placebos; Plasma; Prostaglandins; Proteins; Public Health; Rattus; Reactive Oxygen Species; Relative (related person); Reporting; Research; Research Personnel; Resources; Risk; Safety; Senile Plaques; Site; Source; Standards of Weights and Measures; Surveys; Synaptosomes; System; Testing; Thinking; Thioctic Acid; Time; Tocopherols; Toxic effect; Transgenic Organisms; United States National Institutes of Health; Urine; Vitamin E; Vitamins; aged; cognitive change; day; feeding; hazard; human study; mouse model; nitrate; paired helical filament; prevent; protein aggregate; protein aggregation; response; tau Proteins

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's Disease (AD), a progressive degenerative disease of the brain resulting in impaired memory and loss of cognitive and functional abilities, is the most common cause of dementia in the elderly. It poses a huge public health problem, particularly as life expectancy continues to increase. In the US, the direct and indirect costs of AD were estimated at over $100 billion per year (Ernst 1994). Currently approved treatment for AD includes acetylcholinesterase inhibitors and memantine, both of which target neurotransmitter systems and show symptomatic benefits. There is no disease-modifying treatment to prevent AD or to slow its progression. A major hypothesis about the etiology of AD is that beta-amyloid (A?) aggregates and is deposited in the brain, which leads to neuronal damage and ultimately to AD (reviewed in Hardy 1997). A? ending at residue 42 (A?42) is thought to be the key initiator because A?42 predominates in early amyloid deposits in the brain and has a greater propensity to aggregate, form fibrils, and lead to cellular toxicity than A? ending at residue 40 (A?40) or shorter forms of A?. Oxidative damage is a key factor implicated in the neurodegeneration of AD (Behl 1999) and can be linked to A? (Pratico 1999, Lustbader 2004). The defining neuropathological changes in AD are senile plaques (SP) and neurofibrillary tangles (NFT) made up of paired helical filaments (PHF) comprising insoluble aggregates of the microtubule-associated protein tau. Plaques are surrounded by reactive microglia and astrocytes. Oxidative damage to DNA, lipids, and proteins is readily detected in the brain in AD (Markesbery 1999). Mitochondrial as well as somatic DNA undergoes damage, and the burden of damaged DNA increases with age. Oxidative damage may impair critical neuronal functions in many ways, for example, loss of membrane homeostasis, mitochondrial damage, damage to DNA, and promoting aggregation of proteins such as A? and tau. In addition, reactive oxygen species may act as mediators of apoptosis or programmed cell death, which has been implicated in AD. Many biochemical markers of oxidative damages have been studied, such as nitrated proteins, 8-hydroxy modified forms of DNA or RNA, and 4-OH-nonenal. Among the most stable are isoprostanes, which are forms of prostaglandins produced in response to oxidative stress (Pratico 1999). The F-2 group of isoprostanes is produced in response to oxidative damage to the brain, and reflects lipid peroxidation. Levels of F-2 isoprostanes are increased in the brains of patients with AD, in transgenic mouse models of amyloid deposition, and in the cerebrospinal fluid in AD (Montine 1999 & 2001; Pratico 2000). A specific isoprostane in this group, 8,12-iso iPF2?6, was reported to be increased in plasma and urine in AD (Pratico 2000). Data from many but not all epidemiological studies suggest that dietary or supplemental antioxidants can decrease the risk of AD (e.g. Morris 1998, Paleologos 1998). Although the doses and duration of exposure to antioxidant vitamins varied markedly among participants, the overall effect was in the direction of lower risk of dementia. In the Cache County epidemiological survey, a recent study found that combined use of vitamin E and vitamin C, but not either one alone, was associated with a decreased hazard ration for prevalent and incident AD (Zandi 2004). Some studies have found decreased levels of antioxidants, including vitamin C and E, in patients with AD compared to controls (Polidori 2004). A multi-center controlled clinical trial of patients with moderate to severe AD showed that treatment with 2000 i.u./day of vitamin E (?-tocopherol) delayed the time to reach clinical milestones such as institutionalization, death and loss of activities of daily living (ADL) relative to placebo (Sano 1997). However a recent ADCS clinical trial of patients with MCI found no difference in treatment with vitamin E 2000 i.u./day in delaying clinical progression to AD, compared to placebo. There are many candidate antioxidants, including combinations, which could be neuroprotective in established AD or could have efficacy in prevention of AD. However, testing each of the possibilities in standard clinical trials would be prohibitively expensive. We have therefore decided to examine antioxidant supplements or vitamins which target specific cellular compartments, and look for evidence of biologically relevant effects in AD by measurement of biomarkers in CSF. Combinations of antioxidants: Combinations of antioxidants have been found to be useful in ameliorating oxidative damage in cell culture models and aged dogs (Bondy 2002). In rat cerebral synaptosomes, a combination of ?-tocopherol and vitamin C was more effective in inhibiting formation of isoprostanes than either alone (Montine 2003). Aged dogs develop cognitive changes, accompanied by markers of oxidative damage in their brain, and amyloid deposition in the form of diffuse deposits. In a dog colony studied by Carl Cotman and associates at UC Irvine, a marked decrease in age-associated oxidative markers, as well as lower amyloid load, were seen in the brains of dogs fed a chow supplemented with a combination of antioxidants. Aged dogs who received the supplemented chow showed improvement in their ability to acquire progressively more difficult tasks (e.g. oddity discrimination learning) (Milgram 2002). Support for antioxidant combinations is provided by data from human studies (e.g. Mosci 2002) in which markers of oxidative stress in lymphocytes of older subjects were ameliorated by a combination of antioxidants. Cotman and associates have recently carried out a safety study of vitamin E (?-tocopherol) 800 mg, vitamin C 200 mg and ?-lipoic acid 600 mg given in combination once per day to healthy older individuals for 6 months. No significant adverse events were encountered and the combination was well-tolerated (Cotman, personal communication). Two general cellular compartments where antioxidant supplements may act are the cytosol and mitochondria. While a cocktail of antioxidants that includes both targets would be worth testing, after several rounds of discussions with the ADCS Scientific Advisory panel, we have decided to separately study a combination of antioxidants that act primarily at cytosolic sites (vitamin E + C + ?-lipoic acid) and a single mitochondrial antioxidant, coenzyme Q10.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿尔茨海默病（AD）是一种进行性大脑退行性疾病，会导致记忆力受损以及认知和功能能力丧失，是老年人痴呆症的最常见原因。它造成了巨大的公共卫生问题，特别是随着预期寿命的不断延长。在美国，AD 的直接和间接成本估计每年超过 1000 亿美元（Ernst 1994）。目前批准的 AD 治疗方法包括乙酰胆碱酯酶抑制剂和美金刚，这两种药物都针对神经递质系统并显示出对症状的益处。没有疾病缓解疗法可以预防 AD 或减缓其进展。关于 AD 病因的一个主要假设是 β-淀粉样蛋白 (A?) 聚集并沉积在大脑中，从而导致神经元损伤并最终导致 AD（Hardy 1997 年综述）。一个？以残基 42 结尾的 (A?42) 被认为是关键的引发剂，因为 A?42 在大脑中的早期淀粉样沉积物中占主导地位，并且比 A?42 更容易聚集、形成原纤维并导致细胞毒性。终止于残基40(Aβ40)或更短形式的Aβ。氧化损伤是 AD 神经变性的一个关键因素（Behl 1999），并且可能与 A? （Pratico 1999，Lustbader 2004）。 AD 中定义的神经病理学变化是老年斑 (SP) 和由成对螺旋丝 (PHF) 组成的神经原纤维缠结 (NFT)，其中包含微管相关蛋白 tau 的不溶性聚集体。斑块被反应性小胶质细胞和星形胶质细胞包围。 AD 患者大脑中很容易检测到 DNA、脂质和蛋白质的氧化损伤（Markesbery 1999）。线粒体和体细胞 DNA 都会受到损伤，并且受损 DNA 的负担随着年龄的增长而增加。氧化损伤可能以多种方式损害关键神经元功能，例如膜稳态丧失、线粒体损伤、DNA 损伤以及促进 Aβ 等蛋白质的聚集。和τ。此外，活性氧可能充当细胞凋亡或程序性细胞死亡的介质，这与AD有关。人们已经研究了许多氧化损伤的生化标志物，例如硝化蛋白质、DNA 或 RNA 的 8-羟基修饰形式以及 4-OH-壬烯醛。其中最稳定的是异前列腺素，它是响应氧化应激而产生的前列腺素形式（Pratico 1999）。 F-2 基团的异前列腺素是响应大脑氧化损伤而产生的，反映了脂质过氧化。 AD 患者大脑、淀粉样蛋白沉积转基因小鼠模型以及 AD 脑脊液中 F-2 异前列腺素水平升高（Montine 1999 & 2001；Pratico 2000）。据报道，该组中的一种特定异前列腺素 8,12-iso iPF2?6 在 AD 患者的血浆和尿液中含量增加（Pratico 2000）。 许多但并非全部流行病学研究的数据表明，饮食或补充抗氧化剂可以降低 AD 风险（例如 Morris 1998、Paleologos 1998）。尽管参与者服用抗氧化维生素的剂量和持续时间存在显着差异，但总体效果是降低痴呆风险。在卡什县流行病学调查中，最近的一项研究发现，维生素 E 和维生素 C 的联合使用（而不是单独使用任何一种）与 AD 流行和发病风险比的降低相关（Zandi 2004）。一些研究发现，与对照组相比，AD 患者的抗氧化剂（包括维生素 C 和 E）水平降低（Polidori 2004）。 一项针对中度至重度 AD 患者的多中心对照临床试验表明，每天使用 2000 国际单位的维生素 E（α-生育酚）治疗会延迟达到临床里程碑的时间，例如住院治疗、死亡和日常生活活动能力丧失。 ADL）相对于安慰剂（Sano 1997）。然而，最近一项针对 MCI 患者的 ADCS 临床试验发现，与安慰剂相比，每天 2000 i.u. 维生素 E 治疗在延缓 AD 临床进展方面没有差异。 有许多候选抗氧化剂，包括组合，它们可以对已确诊的 AD 起到神经保护作用，或者可以有效预防 AD。然而，在标准临床试验中测试每种可能性的成本将高得令人望而却步。因此，我们决定检查针对特定细胞区室的抗氧化剂补充剂或维生素，并通过测量脑脊液中的生物标志物来寻找 AD 中生物相关效应的证据。 抗氧化剂的组合： 已发现抗氧化剂的组合可有效改善细胞培养模型和老年狗的氧化损伤（Bondy 2002）。在大鼠大脑突触体中，α-生育酚和维生素 C 的组合比单独使用其中任何一种更能有效地抑制异前列腺素的形成 (Montine 2003)。老年狗会出现认知变化，并伴有大脑氧化损伤标志物和弥漫性沉积物形式的淀粉样蛋白沉积。在加州大学欧文分校的 Carl Cotman 及其同事研究的狗群中，与年龄相关的氧化标记物显着减少，并且淀粉样蛋白负荷降低。 在喂食补充了抗氧化剂组合的食物的狗的大脑中观察到。接受补充饲料的老年狗在完成更困难的任务（例如奇怪辨别学习）的能力方面表现出改善（Milgram 2002）。人体研究数据（例如 Mosci 2002）为抗氧化剂组合提供了支持，其中老年受试者淋巴细胞中的氧化应激标志物通过抗氧化剂组合得到改善。 Cotman 及其同事最近进行了一项安全性研究，将维生素 E（α-生育酚）800 毫克、维生素 C 200 毫克和α-硫辛酸 600 毫克联合给予健康老年人，每天一次，持续 6 个月。没有遇到明显的不良事件，并且该组合具有良好的耐受性（Cotman，个人通讯）。 抗氧化剂补充剂可能发挥作用的两个一般细胞区室是细胞质和线粒体。虽然包含这两个目标的抗氧化剂混合物值得测试，但在与 ADCS 科学咨询小组进行几轮讨论后，我们决定单独研究主要作用于细胞质位点的抗氧化剂组合（维生素 E + C + ?-硫辛酸）和单一线粒体抗氧化剂辅酶 Q10。