Determining Therapeutic Efficacy of AGE in AD

确定 AGE 在 AD 中的治疗效果

• 批准号: 6702792
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6702792
• 关键词: Alzheimer' s disease; amyloid proteins; angiosperms; apoptosis; behavior test; cysteine endopeptidases; dietary supplements; enzyme linked immunosorbent assay; gel mobility shift assay; genetically modified animals; hippocampus; immunocytochemistry; inflammation; interleukin 1; laboratory mouse; neuropathology; neuropsychology; nitric oxide synthase; nuclear factor kappa beta; oxidative stress; plant extracts; tumor necrosis factor alpha

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.

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,甘坦明]; NSAIDS [阿司匹林，布洛芬，吲哚美辛]对炎症进行调节； COX-2抑制剂[Celebrex，Vioxx]。这些药物具有严重的副作用，包括胃肠道出血，肝脏和肾脏毒性，恶心，并且在携带APOE基因1的患者中无效。当前的研究药物包括Xanthine衍生物丙烯酸丙氨酸和降低胆固醇的降低剂[HMG-COA降低剂[HMG-COA还原剂[HMG-COA还原剂抑制了抑制剂抑制剂]。尽管某些他汀类药物被证明是抗淀粉样蛋白的，但由于其促炎性/39，他汀类药物的临床试验很少是无确定性的。 在这方面，具有多效性有用特性且具有不良反应的天然替代性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。一种这样的选择是大蒜。老年大蒜提取物（年龄）包含多能植物化学物质。年龄的s- allyl-cystein（SAC）成分抑制NFKAPPAB，TNFALPHA，IL-1BETA 3、20和INOS/24。我们的初步数据表明，年龄以剂量依赖性方式减少了TG2576中TNFalpha和IL-1Beta。 SAC和Dallyl二硫化物（DADS）年龄的成分是天然HMG-COA还原酶抑制剂34/46。 我们的初步数据表明，年龄减少了Aizheimer的跨Qenic模型（TG2576）中的脑淀粉样蛋白。 此外，已知年龄是自由基清除剂，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-BetA诱导的凋亡并改善鼻鼻涕的记忆缺陷。因此，年龄是一种天然的“ NSAID，他汀类药物，抗氧化剂和抗凋亡剂” - 许多目前用于阿尔茨海默氏症治疗的单一成分合成药物的组合。但是，尚未探讨年龄的有效性作为阿尔茨海默氏症的疗法。该项目旨在确定阿尔茨海默氏症瑞典双突变体（K670M/N671L）模型（TG2576）中年龄的多效性。 假设：在TG2576中，多功能自然替代年龄将预防或逆转类似AD的病理和改善行为缺陷。 具体目的：[1]确定饮食年龄是否会促进非淀粉样蛋白生成的加工并减少TG2576中先前存在的淀粉样蛋白负担； [2]确定饮食年龄是否会减弱TG2576中A-Beta诱导的炎症级联反应； [3]确定饮食年龄是否会抑制TG2576的凋亡； [4]确定饮食年龄是否会改善基于海马的莫里斯水迷宫在TG2576中的表现。 意义：使用胆碱能增强剂和NSAID的当前广告处理由于其不良副作用而受到限制，并且不会改变疾病过程。如果成功的话，该项目将验证使用安全，自然耐受性，具有成本效益和替代性草药药物治疗AD的使用。