Novel flavonoids as anti-inflammatory agents in alcoholism

新型黄酮类化合物作为酒精中毒的抗炎剂

基本信息

批准号：
8251289
负责人：
JOHN M. LITTLETON
金额：
$ 15.09万
依托单位：
NAPROGENIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8251289
关键词：
Affect Affinity Agonist Agreement Alcoholism Alcohols Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apple Arthritis Bacterial Toxins Binding Biological Assay Biological Factors Brain Brain Injuries Cell Line Cells Choline Chronic Clinical Complex Dependence Development Dietary Intervention Drug Addiction Endotoxins Enzyme-Linked Immunosorbent Assay Ethanol Metabolism Evaluation Flavonoids Flavonols Food Fruit Health Benefit In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Investigation Legal patent Libraries Ligands Lipopolysaccharides Lung Marketing Measurement Measures Mediating Mediator of activation protein Medical Methods Microglia Modeling Mus Nerve Degeneration Nicotinic Receptors Nutraceutical Onions Organ Oxidative Stress Peripheral Peritoneal Macrophages Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Plant Extracts Plant Sources Plants Population Prevalence Property Quercetin Receptor Activation Relative (related person)Research Role Solidago Sum Testing Therapeutic Tissues Toxicity Tests Vegetables alcohol exposure commercialization cost design functional food in vitro testing in vivo interest macrophage mouse model neurotoxicity novel novel strategies phase 2 study prevent programs public health relevance radioligand receptor research and development screening therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Flavonoids are ubiquitous secondary metabolites in plants with many known health benefits, which are mostly ascribed to their potent anti-oxidant activity. However, a search for novel nicotinic ligands, using high throughput pharmacological screening of a native plant extract library, and subsequently a pure flavonoid library, led to the highly surprising conclusion that some methoxylated quercetin-like flavonoid derivatives have partial agonist activity, selectively at the alpha7-subtype of nicotinic receptor for acetylcholine (nicAChR). Activation of these receptors on microglia and macrophages is known to reduce the release of inflammatory mediators by these cells, thereby reducing chronic inflammation in the CNS and peripheral tissues. Since there is a wealth of evidence which implicates chronic inflammatory changes in the neurodegeneration and organ damage associated with alcoholism, this implies that these specific flavonoids are of potential value for these therapeutic targets. The same flavonoids have "added value", specifically for alcoholism, in that they retain potent anti-oxidant activity, and so should also protect tissues against the oxidative stress induced by alcohol metabolism. This phase 1 proposal is to investigate the effects of alpha7-nicAChR active flavonoids on bacterial toxin-induced release of inflammatory mediators from microglia and macrophages. The role of alpha7-nicAChRs in any effects seen will be evaluated using selective agonists and antagonists at these receptors. The objective is to identify agents with therapeutic potential, which will be evaluated in more complex models of alcohol-induced tissue damage in vitro and in vivo in phase 2. It is important to note that although the most active flavonoids were discovered in native plants, some of the alpha7-nicAChR active flavonoids in the library are present in common crop plants such as apples and onions. This makes regulatory approval for these flavonoids as "nutraceuticals" or "functional foods" relatively easy to obtain, and limited toxicity testing in phase 2 will be followed by commercialization with a major global food company which has already indicated strong interest in the anti-inflammatory properties of these natural products. PUBLIC HEALTH RELEVANCE: Alcoholism (either dependence or abuse) affects more than 8% of the population of the US, and the societal costs approach $200BN annually. About half of this sum is medical cost, much of which is accrued in treating alcohol-related organ damage. This organ damage is commonly associated with cellular inflammation, and this is also a major contributing factor to alcohol-induced neurodegeneration, which may rival Alzheimer's dementia in its prevalence in the US. Despite this, there are currently no accepted approaches to preventing or reversing this tissue damage. This application proposes a novel approach to organ and brain damage which has major implications for pharmacotherapy of, and/or nutritional intervention in, these therapeutic targets.

描述（由申请人提供）：类黄酮是具有许多已知健康益处的植物中无处不在的次生代谢产物，主要归因于其有效的抗氧化活性。然而，搜索新型的烟碱配体，使用天然植物提取物库的高吞吐药物筛查，然后是纯黄酮素库，得出了令人惊讶的结论，即某些甲氧基化的槲皮素样类黄酮类衍生物具有部分激动剂的活性，可以选择地对Alpha7-sububtype of Acetype of Nicotinicpe nicotinicynicynicynicynicyynicylchol）进行选择。已知这些受体在小胶质细胞和巨噬细胞上的激活可减少这些细胞炎症介质的释放，从而减少中枢神经系统和周围组织的慢性炎症。由于有大量证据暗示着与酒精中毒相关的神经变性和器官损伤的慢性炎症变化，因此这意味着这些特定的类黄酮对这些治疗靶标具有潜在的价值。相同的类黄酮具有“附加价值”，特别是针对酒精中毒的价值，因为它们保留了有效的抗氧化活性，因此还应保护组织免受酒精代谢引起的氧化应激。该第1阶段的建议是研究α7-Nicachr活性类黄酮对细菌毒素诱导的炎症介质从小胶质细胞和巨噬细胞释放的影响。 α7-Nicachrs在所见效应中的作用将使用这些受体的选择性激动剂和拮抗剂进行评估。目的是鉴定具有治疗潜力的药物，将在第2阶段的体外和体内进行更复杂的组织损伤模型中进行评估。重要的是要注意，尽管在本地植物中发现了最活跃的黄酮，但在普通的植物中，图书馆中的某些alpha7-Nicachr活性黄酮在普通的植物中存在于普通植物中，例如Apples and Apples and Apples and Onsions和Oner Onsions。这使得对这些类黄酮的监管批准为“营养素”或“功能性食品”相对容易获得，并且在第2阶段的毒性测试有限，将与一家主要的全球食品公司进行商业化，该公司已经表明对这些天然产物的抗炎特性具有强烈的兴趣。公共卫生相关性：酒精中毒（依赖或虐待）影响美国8％以上的人口，社会成本每年接近2000亿美元。这笔款项的大约一半是医疗费用，其中大部分在治疗与酒精相关的器官损伤方面所累积。这种器官损伤通常与细胞炎症有关，这也是导致酒精诱导的神经变性的主要因素，这可能与阿尔茨海默氏症的痴呆症与美国的患病率相提并论。尽管如此，目前尚无预防或逆转这种组织损害的接受方法。该应用提出了一种新颖的器官和脑损伤方法，该方法对这些治疗靶标的药物治疗和/或营养干预具有重大影响。