Vitamin E Neuroprotection: Novel Molecular Mechanisms

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)。美国人的饮食中缺乏TCT。 TCT在亚洲饮食中含量丰富。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 形式）具有强大的神经保护特性。在痕量浓度 (nM) 下，1-TCT（而非 1-TCP）在体外和体内均具有神经保护作用。显然，维生素 E 家族成员的生物学功能并不多余。当前围绕 1-TCP 安全性和功效的争论需要对天然维生素 E 的所有功能形式进行更均匀的审视。第一个周期的结果得出了这样的假设：12-脂氧合酶 (12-Lox) 是谷氨酸诱导的神经变性的核心，而 1-TCT 调节神经细胞中可诱导的 12-Lox，从而挽救细胞免于死亡。此外，我们假设在 GSH 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，这会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 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假设的体内相关性。目标 1：确定 12-Lox 在细胞神经变性中的重要性以及对 1-TCT 敏感的机制。目标 2：确定体内神经变性中 12-脂氧合酶途径的调节。目标 3：明确维生素 E 在体内大脑中的神经保护意义。长期目标是加深对 1-TCT 依赖性神经保护机制的了解，并据此测试 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 不是合成药物，而是亚洲数百万人每天消耗的安全天然营养素，这一事实使其成为可以快速用于临床前和临床研究的候选者。 叙述 该项目旨在将 1-生育三烯酚（一种美国饮食中很少存在的天然维生素 E）建立为有效对抗中风相关神经组织损伤的饮食成分。

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.