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Determining Therapeutic Efficacy of AGE in AD

确定 AGE 在 AD 中的治疗效果

基本信息

批准号：
6848349
负责人：
NEELIMA CHAUHAN
金额：
$ 19.48万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2006-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Based on the fact that genesis of A-beta derived from amyloidogenic processing of APP is a key event in Alzheimer's pathogenesis including inflammation, and that cholesterol homeostasis and cholinergic system regulate APP processing, current Alzheimer's therapy targets cholinergic enhancement [Tacrine, Aricept/Donezepil, Rivastigmine, Galantamine]; and regulation of inflammation by NSAIDs [Aspirin, Ibuprofen, Indomethacin]; COX-2 inhibitors [Celebrex, Vioxx]. These drugs exert serious side effects including gastrointestinal bleeding, liver and renal toxicity, nausea, and are not effective with patients carrying ApoE gene 1. Current investigational drugs include Xanthine derivatives-Propentofylline and cholesterol-lowering agents [HMG-CoA reductase inhibitors-Statins]. Although some statins are shown to be anti-amyloidogenic, few clinical trials with statins are non-conclusive due to their proinflammatory nature/39. In this respect, natural alternative(s) with pleiotropic useful properties and with least adverse effects may provide greater therapeutic benefit over single-ingredient synthetic pharmaceutical drugs having serious side effects. One such alternative is garlic. Aged garlic extract (AGE) contains multipotent phytochemicals. S-Allyl-Cystein (SAC) component of AGE inhibits NFkAPPAB, TNFalpha, IL-1Beta 3, 20, and iNOS/24. Our preliminary data show that AGE reduced TNFalpha and IL-1Beta in Tg2576 in a dose-dependent manner. SAC and Diallyl disulfide (DADS) components of AGE are natural HMG-CoA reductase inhibitors 34/46. Our preliminary data show that AGE reduced cerebral amyloid in AIzheimer's transqenic model (Tg2576). In addition, AGE is known to be free-radical scavenger that enhances anti-oxidant enzymes (SOD, catalase and glutathione reductase) 3, inhibits lipid peroxidation 20, inhibits A-beta-induced apoptosis and improves memory deficits in senescence-accelerated mice. Thus, AGE is a natural "NSAID, Statin, anti-oxidant and anti-apoptotic agent"-a combination of many single-ingredient synthetic pharmaceutical drugs currently used for Alzheimer's therapy. However, the validity of AGE as Alzheimer's therapy has not been explored. This project is to determine pleiotropic effects of AGE in Alzheimer's Swedish double mutant (K670M/N671L) model (Tg2576). Hypothesis: Multi-potent natural alternative AGE will prevent or reverse AD-like pathology and ameliorate behavioral deficits in Tg2576. Specific Aims: [1] Determine if dietary AGE will promote non-amyloidogenic processing and reduce pre-existing amyloid burden in Tg2576; [2] Determine if dietary AGE will attenuate A-beta-induced inflammatory cascade in Tg2576; [3] Determine if dietary AGE will inhibit apoptosis in Tg2576; [4] Determine if dietary AGE will improve hippocampal-based Morris Water Maze performance in Tg2576. Significance: Current AD-treatment utilizing cholinergic enhancers and NSAIDs is limited due to their adverse side effects and do not modify the disease process. If successful, this project will validate the use of safe, naturally well-tolerated, cost-effective and alternative herbal pharmacotherapy for treating AD.

描述（申请人提供）：基于 APP 淀粉样蛋白形成过程产生的 A-β 的发生是包括炎症在内的阿尔茨海默病发病机制中的关键事件，并且胆固醇稳态和胆碱能系统调节 APP 加工这一事实，当前阿尔茨海默病治疗的目标是胆碱能增强 [他克林、安理申/多奈西匹、卡巴拉汀、卡巴拉汀、加兰他敏]； NSAIDs [阿司匹林、布洛芬、吲哚美辛]调节炎症； COX-2 抑制剂 [Celebrex、Vioxx]。这些药物会产生严重的副作用，包括胃肠道出血、肝肾毒性、恶心，并且对携带ApoE基因1的患者无效。目前在研药物包括黄嘌呤衍生物-丙茶碱和降胆固醇药物[HMG-CoA还原酶抑制剂-他汀类药物]。尽管一些他汀类药物被证明具有抗淀粉样蛋白生成作用，但由于其促炎性质，很少有他汀类药物的临床试验是非结论性的/39。在这方面，具有多效性有用特性且副作用最小的天然替代品可以比具有严重副作用的单一成分合成药物提供更大的治疗益处。其中一种替代品是大蒜。陈蒜提取物 (AGE) 含有多效植物化学物质。 AGE 的 S-烯丙基-半胱氨酸 (SAC) 成分可抑制 NFkAPPAB、TNFα、IL-1Beta 3、20 和 iNOS/24。我们的初步数据表明，AGE 以剂量依赖性方式减少 Tg2576 中的 TNFα 和 IL-1Beta。 AGE 的 SAC 和二烯丙基二硫化物 (DADS) 成分是天然的 HMG-CoA 还原酶抑制剂 34/46。我们的初步数据表明，AGE 减少了艾茨海默氏跨基因模型 (Tg2576) 中的脑淀粉样蛋白。此外，AGE 被认为是自由基清除剂，可增强抗氧化酶（SOD、过氧化氢酶和谷胱甘肽还原酶）3、抑制脂质过氧化 20、抑制 A-β 诱导的细胞凋亡并改善加速衰老小鼠的记忆缺陷。因此，AGE是一种天然的“NSAID、他汀类、抗氧化剂和抗凋亡剂”——目前用于治疗阿尔茨海默病的许多单一成分合成药物的组合。然而，AGE 作为阿尔茨海默病治疗的有效性尚未得到探索。该项目旨在确定 AGE 在阿尔茨海默病瑞典双突变体 (K670M/N671L) 模型 (Tg2576) 中的多效性作用。假设：多效天然替代 AGE 将预防或逆转 AD 样病理并改善 Tg2576 的行为缺陷。具体目标： [1] 确定膳食 AGE 是否会促进非淀粉样蛋白生成过程并减少 Tg2576 中预先存在的淀粉样蛋白负担； [2] 确定膳食 AGE 是否会减弱 Tg2576 中 A-β 诱导的炎症级联反应； [3]确定膳食AGE是否会抑制Tg2576细胞凋亡； [4] 确定膳食 AGE 是否会改善 Tg2576 中基于海马的莫里斯水迷宫表现。意义：目前使用胆碱能增强剂和非甾体抗炎药的 AD 治疗因其不良副作用而受到限制，并且不能改变疾病进程。如果成功，该项目将验证使用安全、自然耐受性良好、具有成本效益的替代草药疗法来治疗 AD。