Potential anti-relapse drugs: a plant genomics approach

描述(申请人提供)：酒精引起的神经变性和随后的痴呆是酒精中毒的重要治疗靶点。然而，由于酒精引起的神经毒性在酒精存在和戒酒期间具有不同的机制，这些都是药物治疗的困难靶点。根据临床前的研究，两种类型的神经保护化合物，有效的抗氧化剂，和乙酰胆碱的尼古丁受体激动剂(Nicotinic Receptor for Acylylchine，NicAChRs)似乎特别适合这一治疗挑战。作为最初的第二阶段STTR项目(“抗复发药物，植物基因组学方法”)一个次要的特定目标的一部分，我们发现了一种来自本土植物的新的天然产品，一枝黄花，具有这两个特征，并且在简单的细胞培养模型中对酒精诱导的毒性具有高度的保护作用。这被初步鉴定为甲基槲皮黄素，以前还没有从这种植物中提取的化合物或具有类似槲皮素类似结构的化合物在α7-NicAChRs上具有活性或对抗这种类型的神经毒性的报道。最初的项目(专注于抗复发特性)并不是为了研究神经保护活性。在NOT-OD-09-058计划下，“NIH宣布恢复法案资金可用于竞争性修订应用”，我们现在建议进一步对该化合物进行药理学表征，并在体外模型和体内发育啮齿动物模型中评估其针对酒精的神经毒性影响的治疗潜力。除了这种传统的方法，我们还建议使用一种基于该化合物的细胞保护抗氧化性的选择程序来产生过量产生这种活性的突变植物细胞培养物。这不是最初提议的一部分，因为我们不知道我们会发现一种结合了这些特性的结构！这一补充将使我们能够聘请两名博士后研究人员来进行额外的研究，并将使我们能够加快这种新的神经保护剂在酒精中毒中的研究。对于NIAAA和NIH来说，开发治疗酒精中毒的新药是一个明确的优先事项。 公共卫生相关性：通知编号(NOT-OD-09-058)和通知标题：美国国立卫生研究院宣布恢复法案资金可用于竞争性修订申请与酒精中毒相关的痴呆症是一个主要的但基本上未被认识到的临床问题，在美国的发病率可能与阿尔茨海默氏症相当。目前还没有公认的治疗方法，这可能影响了这种疾病的低诊断率。基础研究表明，两种类型的药理活性最具潜在的治疗价值，而且，在某种程度上偶然的是，我们发现了一种似乎同时具有这两种特性的天然产物分子。这项提议是为了更全面地描述这种分子，并开始评估其作为治疗酒精中毒的神经保护药物的潜力。由于最终治疗酒精中毒的最佳方法是显著减少饮酒量，我们预计该产品将被用作旨在戒酒的药物治疗和行为计划的一部分，或从病理水平上减少酒精消耗量。

DESCRIPTION (provided by applicant): Alcohol-induced neurodegeneration and the consequent dementia are important therapeutic targets in alcoholism. However, because alcohol-induced neurotoxicity has different mechanisms during the presence of alcohol and during its withdrawal, these are difficult targets for pharmacotherapy. Based on preclinical research, two types of neuroprotective compound, potent anti-oxidants, and agonists at alpha7 nicotinic receptors for acetylcholine (nicAChRs) are agents which seem particularly well-suited to this therapeutic challenge. As part of a minor specific aim in the original phase 2 STTR project ("Anti-relapse agents, a plant genomics approach") , we have discovered a novel natural product from the native plant, Solidago nemoralis, which has both of these characteristics, and which is highly protective against alcohol-induced toxicity in simple cell culture models. This is tentatively identified as a methyl quercetagetin, and there are no previous reports of compounds from this plant species, or with similar quercetin-like structures, being active at alpha7-nicAChRs, or against this type of neurotoxicity. The original project (which focused on anti-relapse properties) was not designed to investigate neuroprotective activity. Under the program NOT-OD-09-058, "NIH announces the availability of Recovery Act funds for competitive revision applications" we now propose to pharmacologically characterize this compound further, and to evaluate its therapeutic potential against the neurotoxic effects of alcohol, both in in vitro models, and in a developmental rodent model in vivo. In addition to this conventional approach, we also propose to use a selection procedure, based on the cytoprotective anti-oxidant properties of this compound, to generate mutant plant cell cultures which overproduce this activity. This was not a part of the original proposal because we had no idea that we would discover a structure which combined these properties! This supplement will enable us to employ two postdoctoral researchers to cover the additional research, and will enable us to accelerate the investigation of this novel neuroprotective agent in alcoholism. The development of novel medications for alcoholism is a stated priority for NIAAA and for NIH. PUBLIC HEALTH RELEVANCE: Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications The dementia associated with alcoholism is a major, but largely unrecognized, clinical problem, probably rivaling Alzheimer's Dementia in incidence in the USA. There are no recognized treatments, and this probably impacts the low rate of diagnosis of the condition. Basic research suggests that two types of pharmacological activity are of most potential therapeutic value and, somewhat serendipitously, we have discovered a natural product molecule which appears to have both of these properties. This proposal is to characterize this molecule more fully, and to begin to evaluate its potential as a neuroprotective drug in alcoholism. Since ultimately the best treatment for alcoholism is a marked reduction in consumption, we envisage this product being used as a part of a pharmacotherapeutic and behavioral program aimed at abstinence, or at a reduction of alcohol consumption from pathological levels.