Vitamin E Neuroprotection: Novel Molecular Mechanisms

维生素 E 神经保护：新颖的分子机制

• 批准号: 7547006
• 负责人: Chandan K Sen
• 金额: $ 26.25万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547006
• 关键词: 12-HETE; Abbreviations; American; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Asia; Asians; Attention; Attenuated; Biological Process; Brain; Brain Injuries; Cause of Death; Cell Death; Cells; Cessation of life; Clinical; Clinical Research; Cysteine; Cystine; Diet; Dinoprostone; Disease; Family; Funding; Generations; Genetic Models; Glutamates; Health; Hippocampus (Brain); Human; In Vitro; Injury; Light; Membrane; Microinjections; Mitochondria; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Oxidants; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Play; Property; Protein Deficiency; Regulation; Research; Research Personnel; Resistance; Role; Safety; Stroke; Techniques; Terminology; Testing; Time; Tissues; Tocopherols; Tocotrienols; Toxic effect; Vitamin E; Vitamins; Work; base; efficacy testing; excitotoxicity; in vivo; inhibitor/antagonist; knock-down; member; neuroprotection; novel; pre-clinical; prevent; relating to nervous system; 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具有强大的神经保护特性。从历史上看，这一信息完全来自对1-生育酚的研究。在自然界中，维生素E家族由八个成员组成，分别为生育酚(Tcp)和生育三烯醇(TCT)。美国人的饮食中缺乏TCT。TCT在亚洲饮食中含量丰富。该项目第一周期的研究首次证明，1-TCT是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)的1-TCT在体外和体内均具有神经保护作用，而1-Tcp无此作用。很明显，维生素E家族的成员在其生物学功能方面并不是多余的。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公平的研究。第一个周期的结果导致了这样的假设：12-脂氧合酶(12-Lox)是谷氨酸诱导的神经退化的中心，1-TCT调节神经细胞中可诱导的12-Lox，使细胞免于死亡。此外，我们假设在GSH缺乏的条件下(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。目标1侧重于细胞机制，而目标2和3使用12-Lox(12-Lox-/-，目标2)和维生素E(TTP-/-，目标3；TTP=生育酚转移蛋白)缺乏的遗传模型来检验我们假设的体内相关性。目的1：探讨12-Lox在细胞神经退行性变中的意义及其对1-TCT的敏感机制。目的2：探讨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：明确维生素E在活体脑内的神经保护意义。长期目标是了解1-TCT依赖神经保护的潜在机制，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有效性。事实上，1-TCT不是一种合成药物，而是一种安全的天然营养物质，在亚洲数百万人每天都在消费，这使得它成为一个可以迅速应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，一种在美国饮食中很少存在的天然维生素E，作为一种有效预防中风相关的神经组织损伤的饮食成分。