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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 阿尔茨海默氏病（AD）是大脑的进行性退行性疾病，导致记忆力受损，认知和功能能力的丧失是老年痴呆症的最常见原因。它带来了一个巨大的公共卫生问题，尤其是随着预期寿命的持续增加。在美国，AD的直接和间接费用估计为每年超过1000亿美元（Ernst 1994）。目前对AD的批准治疗包括乙酰胆碱酯酶抑制剂和美金刚蛋白，它们均靶向神经递质系统并显示出症状的好处。没有改善疾病的治疗方法可以防止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？）聚集体并沉积在大脑中，这会导致神经元损害并最终导致AD（在Hardy 1997中进行了综述）。一个？以残基42（A？42）结尾，被认为是关键的引发剂，因为A？42在大脑早期的淀粉样蛋白沉积物中占主导地位，并且比A更大的倾向，形成原纤维并导致细胞毒性比A？以残留物40（A？40）或较短的A？结尾。氧化损伤是关键因素与AD的神经变性有关（Behl 1999），并且可以与A相关。 （Pratico 1999，Lustbader 2004）。 AD的定义神经病理学变化是由成对的螺旋丝（PHF）组成的老年斑块（SP）和神经原纤维缠结（NFT），其中包括微管相关蛋白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。在AD中，在大脑中很容易检测到对DNA，脂质和蛋白质的氧化损伤（Markesbery 1999）。线粒体和体细胞DNA受到损害，而受损DNA的负担随着年龄的增长而增加。氧化损伤可能会在许多方面损害关键神经元功能，例如，膜稳态的丧失，线粒体损伤，对DNA损伤以及促进蛋白质（例如A）的聚集？和tau。此外，活性氧可能是凋亡或程序性细胞死亡的介体，这与AD有关。已经研究了许多氧化损伤的生化标志物，例如硝化蛋白，8-羟基修饰形式的DNA或RNA以及4-OH-非nonenal。最稳定的是异前列腺，它们是响应氧化应激而产生的前列腺素的形式（Pratico 1999）。 F-2组异前列腺是根据对大脑氧化损伤的响应而产生的，并反映了脂质过氧化。 AD患者的大脑，淀粉样蛋白沉积的转基因小鼠模型以及AD中的脑脊液中的F-2等前列体水平升高（Montine 1999＆2001； Pratico 2000）。据报道，该组的特定异丙烷是8,12-ISO IPF2？6，在AD中的血浆和尿液中增加了（Pratico 2000）。 来自许多但并非所有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的风险（例如Morris 1998，Paleologos 1998）。尽管参与者的剂量和暴露于抗氧化剂维生素的持续时间差异很大，但总体作用是降低痴呆症风险的方向。在Cache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的合并使用（但不是一个人）与普遍存在和事件AD的危害降低有关（Zandi 2004）。一些研究发现，与对照组相比，AD患者的抗氧化剂水平降低了，包括维生素C和E（Polidori 2004）。 对中度至重度AD患者的多中心对照临床试验表明，维生素E（？ - 托酚）的2000 I.U./天数延迟了达到临床里程碑的时间，例如相对于安慰剂的制度化，死亡和日常生活活动（ADL）的活动（Sano 1997）。然而，与安慰剂相比，MCI患者最近进行的ADCS临床试验发现，维生素E 2000 I.U./DAY在延迟临床进展方面没有差异。 有许多候选抗氧化剂，包括组合，它们可以在已建立的AD中具有神经保护作用，或者可以预防AD的功效。但是，测试标准临床试验中的每种可能性将非常昂贵。因此，我们决定检查针对特定细胞室的抗氧化剂补充剂或维生素，并通过测量CSF中的生物标志物来寻找AD中生物学相关作用的证据。 抗氧化剂的组合： 已经发现，抗氧化剂的组合可用于改善细胞培养模型和老年狗的氧化损伤（Bondy 2002）。在大鼠脑突触体中，与单独使用的 - 托林C和维生素C的组合在抑制异前列腺的形成方面更有效（Montine 2003）。老年狗会发生认知变化，并伴有大脑中氧化损伤的标志物，并以弥漫性沉积的形式淀粉样蛋白沉积。在Carl Cotman和UC Irvine的同事研究的狗殖民地中，与年龄相关的氧化标志物以及较低的淀粉样蛋白负载明显下降是 在喂食含有抗氧化剂组合的食物的狗的大脑中可见。接受补充的Chow的老年狗表现出其逐渐获得更艰巨的任务的能力（例如，奇怪的歧视学习）（Milgram 2002）。人类研究的数据（例如Mosci 2002）提供了对抗氧化剂组合的支持，在该数据中，通过抗氧化剂的组合可以改善老年受试者淋巴细胞中氧化应激的标志物。 Cotman and Assoses最近对维生素E（？ - 生育酚）800 mg，维生素C 200 mg和？脂肪酸进行了安全研究，每天对健康的老年人组合一次600 mg，持续6个月。没有遇到重大的不良事件，并且结合良好（Cotman，个人交流）。 抗氧化剂补充剂可能起作用的两个通用细胞室是细胞质和线粒体。虽然包括两个靶标的抗氧化剂鸡尾酒都值得测试，但在与ADCS科学咨询小组进行了几轮讨论之后，我们决定分别研究主要在细胞胞浆位点起作用的抗氧化剂（维生素E + C +？脂肪酸）和单位线粒体的抗核心抗抗氧化剂，QYENSIMENSEME，Q10 Q10。