Vitamin E Neuroprotection: Novel Molecular Mechanisms

维生素 E 神经保护：新颖的分子机制

• 批准号: 7752535
• 负责人: Chandan K Sen
• 金额: $ 25.99万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752535
• 关键词: 12-HETE; ATP Synthesis Pathway; Abbreviations; American; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Asia; Asians; Astrocytes; Attention; Attenuated; Biological Process; Brain; Cell Death; Cell membrane; Cells; Cessation of life; Clinical; Companions; Cysteine; Cystine; Dendritic Cells; Dextrans; Diet; Dinoprostone; Disease; Dyes; Ethanol; Family; Figs - dietary; Free Radicals; Funding; Generations; Genetic Models; Glial Fibrillary Acidic Protein; Glutamates; Health; Hippocampus (Brain); IL2RA gene; In Vitro; Incubated; Infarction; Injury; Light; Membrane Potentials; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Monitor; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofilament-M; Neurons; Nutrient; Oxidants; Oxidative Stress; Oxygen Consumption; Pathway interactions; Pharmaceutical Preparations; Play; Property; Protein Deficiency; Proteins; Rattus; Regulation; Research; Research Personnel; Resistance; Respiration; Role; Safety; Solutions; Stroke; Succinates; Testing; Time; Tissue Sample; Tissues; Tocopherols; Tocotrienols; Toxic effect; Vitamin E; Vitamins; Work; astrogliosis; base; brain tissue; consumption measures; dextran; efficacy testing; excitotoxicity; in vivo; inhibitor/antagonist; knock-down; member; neuroprotection; novel; pre-clinical; prevent; programs; relating to nervous system; research study; response; tool

DESCRIPTION (provided by applicant): Vitamin E has potent neuroprotective properties. Historically, this information has been derived entirely from the study of 1-tocopherol. In nature, the vitamin E family consists of eight members categorized as tocopherols (TCP) and tocotrienols (TCT). The American diet is deficient in TCT. TCT is abundant in Asian diet. Studies during the first cycle of this project presented first evidence establishing that 1-TCT, a poorly known form of natural vitamin E, possesses potent neuroprotective properties. At trace concentration (nM) 1- TCT, but not 1-TCP, conferred neuroprotection in vitro as well as in vivo. It is clear that members of the vitamin E family are not redundant with respect to their biological functions. Current debate surrounding the safety and efficacy of 1-TCP warrants a more even look at all functional forms of natural vitamin E. Results of the first cycle led to the hypothesis that 12-lipoxygenase (12-Lox) is central to glutamate- induced neurodegeneration and that 1-TCT regulates inducible 12-Lox in neural cells rescuing the cells from death. Furthermore, we hypothesize that under GSH-deficient conditions (as is seen during numerous neurodegenerative conditions), arachidonic acid (AA) is metabolized by 12-Lox to 12-HPETE which compromises mitochondrial function and causes neural damage. Aim 1 focuses on cellular mechanisms while Aims 2&3 employs genetic models of 12-Lox (12-Lox-/-, Aim 2) as well as vitamin E (TTP-/-, Aim 3; TTP= tocopherol transfer protein) deficiency to test the in vivo relevance of our hypotheses. Aim 1: Establish the significance of 12-Lox in cellular neurodegeneration and the mechanisms sensitive to 1-TCT. Aim 2: Determine the regulation of 12-lipoxygenase pathway in neurodegeneration in vivo. Aim 3: Define the neuroprotective significance of vitamin E in the brain in vivo. The long-term objective is to develop an understanding of the mechanisms underlying 1-TCT- dependent neuroprotection and in that light to test the efficacy of 1-TCT in protecting against neurodegenerative disorders in preclinical and clinical settings. The fact that 1-TCT is not a synthetic drug but a safe natural nutrient consumed by millions of people on a daily basis in Asia makes it a candidate that could be rapidly taken to pre-clinical and clinical studies.NARRATIVE The project seeks to establish 1-tocotrienol, a natural vitamin E poorly present in American diet, as a dietary ingredient effective against stroke-related damage to the neural tissue.

描述（由申请人提供）：维生素E具有有效的神经保护特性。从历史上看，这些信息完全来自于对1-生育酚的研究。在自然界中，维生素E家族由8个成员组成，分别是生育酚（TCP）和生育三烯醇（TCT）。美国人的饮食缺乏TCT。亚洲饮食中含有丰富的TCT。该项目第一个周期的研究提供了第一个证据，证明1-TCT，一种鲜为人知的天然维生素E，具有强大的神经保护特性。微量浓度（nM） 1- TCT，而不是1- tcp，在体外和体内都具有神经保护作用。显然，维生素E家族的成员就其生物功能而言并不是多余的。目前围绕1-TCP的安全性和有效性的争论需要对天然维生素e的所有功能形式进行更深入的研究。第一个周期的结果导致了12-脂氧合酶（12-Lox）对谷氨酸诱导的神经变性至关重要的假设，1-TCT调节神经细胞中诱导的12-Lox，使细胞免于死亡。此外，我们假设在谷胱甘肽缺乏的情况下（如在许多神经退行性疾病中所见），花生四烯酸（AA）被12-Lox代谢为12-HPETE，从而损害线粒体功能并导致神经损伤。Aim 1侧重于细胞机制，而Aims 2和3采用12-Lox （12-Lox-/-, Aim 2）和维生素E （TTP-/-, Aim 3； TTP=生育酚转移蛋白）缺乏的遗传模型来测试我们假设的体内相关性。目的1：确定12-Lox在细胞神经退行性变中的意义及对1- tct敏感的机制。目的2：确定12-脂氧合酶途径在体内神经退行性变中的调节作用。目的3：明确体内维生素E对大脑的神经保护作用。长期目标是了解1-TCT依赖性神经保护的机制，并在此基础上测试1-TCT在临床前和临床环境中预防神经退行性疾病的功效。事实上，1-TCT不是一种合成药物，而是一种安全的天然营养素，在亚洲每天有数百万人食用，这使它成为一种可以迅速用于临床前和临床研究的候选药物。该项目旨在建立1-生育三烯醇，一种天然维生素E，在美国人的饮食中很少存在，作为一种有效防止中风相关神经组织损伤的膳食成分。