Novel flavonoids as anti-inflammatory agents in alcoholism

描述（由申请人提供）：黄酮类化合物是植物中普遍存在的次级代谢产物，具有许多已知的健康益处，这主要归因于其有效的抗氧化活性。 然而，使用天然植物提取物文库的高通量药理学筛选以及随后的纯类黄酮文库来搜索新的烟碱配体，得到了非常令人惊讶的结论，即一些甲氧基化的槲皮素样类黄酮衍生物具有部分激动剂活性，选择性地在乙酰胆碱的烟碱受体（nicAChR）的α 7亚型上。 已知小胶质细胞和巨噬细胞上的这些受体的活化减少这些细胞释放炎性介质，从而减少CNS和外周组织中的慢性炎症。 由于有大量的证据表明慢性炎症性变化与酒精中毒相关的神经变性和器官损伤，这意味着这些特定的黄酮类化合物是这些治疗靶点的潜在价值。 同样的黄酮类化合物具有“附加值”，特别是对于酒精中毒，因为它们保留了有效的抗氧化活性，因此也应该保护组织免受酒精代谢引起的氧化应激。 本阶段1的建议是研究α 7-nicAChR活性黄酮类化合物对细菌毒素诱导的小胶质细胞和巨噬细胞释放炎症介质的影响。 将使用这些受体的选择性激动剂和拮抗剂来评价α 7-nicAChR在所观察到的任何效应中的作用。 目的是确定具有治疗潜力的药物，将在2期的体外和体内酒精诱导的组织损伤的更复杂模型中进行评估。 值得注意的是，尽管最活跃的类黄酮是在原生植物中发现的，但库中的一些α 7-nicAChR活性类黄酮存在于苹果和洋葱等常见作物中。 这使得这些黄酮类化合物作为“营养保健品”或“功能食品”的监管批准相对容易获得，并且在第二阶段的有限毒性测试之后将与一家主要的全球食品公司进行商业化，该公司已经表示对这些天然产品的抗炎特性有浓厚的兴趣。 公共卫生相关性： 酒精中毒（依赖或滥用）影响了美国8%以上的人口，每年的社会成本接近2000亿美元。 其中大约一半是医疗费用，其中大部分是在治疗与酒精有关的器官损伤时积累的。 这种器官损伤通常与细胞炎症有关，这也是酒精诱导的神经变性的主要因素，酒精诱导的神经变性在美国的流行率可能与阿尔茨海默氏痴呆症相当。 尽管如此，目前还没有可接受的方法来预防或逆转这种组织损伤。 本申请提出了一种针对器官和脑损伤的新方法，其对这些治疗靶标的药物治疗和/或营养干预具有重要意义。

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.