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家族由八个归类为生育酚（TCP）和生育三烯酚（TCT）的成员组成。美国饮食缺乏TCT。 TCT在亚洲饮食中很丰富。该项目的第一个周期期间的研究提出了第一个证据，表明1-TCT是一种已知的天然维生素E形式，具有有效的神经保护特性。在痕量浓度（NM）1-TCT时，而不是1-TCP，在体外和体内赋予了神经保护作用。显然，维生素E家族的成员在其生物学功能方面并不多余。围绕1-TCP的安全性和功效的当前辩论甚至更加考虑到自然维生素E的所有功能形式。第一个周期的结果导致假设，即12-脂氧合酶（12-lox）对谷氨酸诱导的神经变性是核心，并且1-TCT调节可诱导的12-lox在神经细胞中可诱导的12-lox促进神经细胞，从而促进了死亡的细胞。此外，我们假设在缺乏GSH的条件下（如在许多神经退行性条件下看到），花生四烯酸（AA）被12-lox降低到12-HPETE，从而损害了线粒体功能并造成神经损伤。 AIM 1专注于细胞机制，而目标2和3采用12-Lox（12-Lox - / - ，AIM 2）的遗传模型以及维生素E（TTP - / - ，AIM 3; TTP = TTP = TTP = TTP = TTP = TOCOPHEROL转移蛋白）缺陷来测试我们假设的体内相关性。 AIM 1：确定12-Lox在细胞神经变性中的重要性和对1-TCT敏感的机制。 AIM 2：确定体内神经变性中12-脂氧合酶途径的调节。 AIM 3：定义体内脑中维生素E的神经保护意义。长期目标是对1-TCT依赖性神经保护的机制发展了解1-TCT在预防临床前和临床环境中神经退行性疾病方面的功效。 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.