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具有有效的神经保护特性。从历史上看，这些信息完全来自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，分为生育酚（TCP）和生育三烯酚（TCT）。美国人的饮食缺乏TCT。TCT在亚洲饮食中很丰富。在该项目的第一个周期期间进行的研究提出了第一个证据，证明1-TCT（一种鲜为人知的天然维生素E形式）具有有效的神经保护特性。在痕量浓度（nM）1- TCT，但不是1-TCP，赋予神经保护在体外以及在体内。很明显，维生素E家族的成员就其生物学功能而言并非多余。目前围绕1-TCP的安全性和有效性的争论，需要更公平地看待天然维生素E的所有功能形式。第一个周期的结果导致了这样的假设，即12-脂氧合酶（12-Lox）是谷氨酸诱导的神经变性的中心，并且1-TCT调节神经细胞中的诱导型12-Lox，拯救细胞免于死亡。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，这损害了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&3采用12-Lox（12-Lox-/-，目标2）以及维生素E（TTP-/-，目标3; TTP=生育酚转移蛋白）缺乏的遗传模型来测试我们的假设的体内相关性。目的1：探讨12-Lox在神经细胞变性中的意义及1-TCT敏感性的机制。目的2：探讨12-脂氧合酶途径在神经元退行性变中的调控作用。目的3：明确维生素E在体内脑内的神经保护作用。长期目标是了解1-TCT依赖性神经保护的机制，并在临床前和临床环境中测试1-TCT在保护神经退行性疾病方面的功效。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，这使它成为一种候选药物，可以迅速进入临床前和临床研究。叙述该项目旨在建立1-生育三烯酚，一种在美国饮食中缺乏的天然维生素E，作为一种有效对抗中风相关神经组织损伤的饮食成分。