NATURAL VITAMIN E FORMS AS ANTI-INFLAMMATORY DRUGS

天然维生素 E 形式作为抗炎药物

• 批准号: 6702786
• 负责人: Bruce N Ames
• 金额: $ 35.22万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702786
• 关键词: alternative medicine; antiinflammatory agents; aspirin; combination chemotherapy; drug interactions; drug screening /evaluation; eicosanoid metabolism; eicosanoids; inflammation; laboratory rat; nonhuman therapy evaluation; nutrition related tag; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; tissue /cell culture; tocopherols; vitamin therapy

DESCRIPTION (provided by applicant): Chronic inflammation constitutes one of the major etiologies of degenerative diseases including cancer, and cardiovascular and neurodegenerative diseases; chronic inflammation also contributes to rheumatoid arthritis, asthma and hepatitis. These diseases are among the leading causes of death and disability in the world. During inflammation, several pro-inflammatory mediators including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), as well as cytokines, such as TNF-alpha, play central roles in regulating inflammatory response and inflammation-mediated damage. Vitamin E comprises eight structurally related molecules, alpha-,beta-, gamma-, delta-tocopherol, and alpha-,beta-, gamma-, delta -tocotrienol. Among them, only alpha -tocopherol (alphaT) has been extensively studied. Recent studies indicate that other forms of vitamin E have unique properties, which are not shared by alphaT, but are important to human disease prevention and therapy. Gamma-Tocopherol (gammaT) and its metabolite, but not aT, exhibit anti-inflammatory effects by inhibiting cyclooxygenase (COX)- catalyzed formation of PGE2. In a rat inflammation model, gammaT inhibits not only PGE2, but also LTB4, and TNF-alpha. These results suggest that gammaT may be superior to some commonly used non-steroid anti-inflammatory drugs (NSAIDs), such as COX inhibitors, most of which only inhibit the COX-mediated pathway. Preliminary studies also indicate that delta- tocopherol and gamma-tocotrienol, compared with gammaT, are even stronger inhibitors of the COX-catalyzed formation of PGE2. These observations led to the current hypothesis that certain forms of vitamin E and their combinations have unique pharmaceutical utility as anti-inflammatory drugs, or as supplements that complement and improve current treatments for inflammatory diseases. This hypothesis will be tested by pursuit of the following Specific Aims in cell culture and animal experiments: 1. Investigate in vitro anti-inflammatory properties of individual vitamin E forms and their combinations; 2. Investigate and compare in vivo anti-inflammatory activities of individual vitamin E forms and their combinations; and 3. Investigate the potentially improved effects of combining certain forms of vitamin E and NSAIDs, such as aspirin, in a rat inflammation model. Our studies may lead to the discovery of novel and better therapy for treating and preventing inflammatory diseases, and provide the scientific rationale, the experimental evidence and the biochemical basis for future human studies.

描述（申请人提供）：慢性炎症是包括癌症、心血管和神经退行性疾病在内的退行性疾病的主要病因之一；慢性炎症还会导致类风湿性关节炎、哮喘和肝炎。这些疾病是世界上死亡和残疾的主要原因之一。在炎症过程中，前列腺素 E2 (PGE2) 和白三烯 B4 (LTB4) 等多种促炎介质以及 TNF-α 等细胞因子在调节炎症反应和炎症介导的损伤中发挥着核心作用。维生素 E 包含八种结构相关的分子：α-、β-、γ-、δ-生育酚和 α-、β-、γ-、δ-生育三烯酚。其中，只有α-生育酚（alphaT）得到了广泛的研究。最近的研究表明，其他形式的维生素 E 具有 alphaT 不具备的独特性质，但对人类疾病的预防和治疗很重要。 γ-生育酚 (gammaT) 及其代谢物（但不是 aT）通过抑制环氧合酶 (COX) 催化的 PGE2 形成而表现出抗炎作用。在大鼠炎症模型中，gammaT 不仅抑制 PGE2，还抑制 LTB4 和 TNF-α。这些结果表明，gammaT 可能优于一些常用的非类固醇抗炎药 (NSAID)，例如 COX 抑制剂，其中大多数仅抑制 COX 介导的途径。初步研究还表明，与 gammaT 相比，δ-生育酚和 γ-生育三烯酚是 COX 催化的 PGE2 形成的更强抑制剂。这些观察结果得出了当前的假设，即某些形式的维生素 E 及其组合具有独特的药物用途，可作为抗炎药，或作为补充和改善当前炎症性疾病治疗的补充剂。这一假设将通过在细胞培养和动物实验中追求以下具体目标来检验： 1. 研究单个维生素 E 形式及其组合的体外抗炎特性； 2. 研究并比较维生素E单独形式及其组合的体内抗炎活性； 3. 研究在大鼠炎症模型中联合使用某些形式的维生素 E 和 NSAID（例如阿司匹林）的潜在改善效果。我们的研究可能会发现治疗和预防炎症性疾病的新的、更好的疗法，并为未来的人类研究提供科学原理、实验证据和生化基础。