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: 7062439
• 负责人: Qing Jiang
• 金额: $ 33.44万
• 依托单位: PURDUE UNIVERSITY
• 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/7062439
• 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（由申请人提供）：慢性炎症是退行性疾病（包括癌症、心血管和神经退行性疾病）的主要病因之一;慢性炎症还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，包括前列腺素E2（PGE 2）和白三烯B4（LTB 4）在内的几种促炎介质以及细胞因子（如TNF-α）在调节炎症反应和炎症介导的损伤中发挥核心作用。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）已被广泛研究。最近的研究表明，其他形式的维生素E具有独特的性质，这些性质不是alphaT所共有的，但对人类疾病的预防和治疗很重要。γ-生育酚（γ T）及其代谢产物（但不是aT）通过抑制环氧合酶（考克斯）催化的PGE 2形成而表现出抗炎作用。在大鼠炎症模型中，γ T不仅抑制PGE 2，还抑制LTB 4和TNF-α。这些结果表明，γ T可能是上级一些常用的非甾体抗炎药（NSAID），如考克斯抑制剂，其中大多数只抑制COX介导的途径。初步研究还表明，与γ T相比，δ-生育酚和γ-生育三烯酚甚至是COX催化形成PGE 2的更强抑制剂。这些观察结果导致了目前的假设，即某些形式的维生素E及其组合作为抗炎药物或补充剂具有独特的药用价值，可以补充和改善目前对炎症性疾病的治疗。这一假设将通过在细胞培养和动物实验中追求以下特定目的来检验：1.研究单个维生素E形式及其组合的体外抗炎特性; 2.研究和比较单个维生素E形式及其组合的体内抗炎活性;以及3.在大鼠炎症模型中研究某些形式的维生素E和NSAID（如阿司匹林）联合使用的潜在改善作用。我们的研究可能会发现新的和更好的治疗和预防炎症性疾病的治疗方法，并为未来的人体研究提供科学依据，实验证据和生化基础。