Alcohol, the vagus nerve and multi-organ inflammation

酒精、迷走神经和多器官炎症

基本信息

批准号：
8064072
负责人：
JOHN M. LITTLETON
金额：
$ 16.51万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064072
关键词：
Acetylcholine Acute Affect Affinity Agonist Alcohol-Induced Disorders Alcoholism Alcohols Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Brain Cell physiology Cells Choline Chronic Consumption Dependence Development Drug Evaluation Endotoxins Exploratory/Developmental Grant Heart Rate In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knock-out Knockout Mice Libraries Ligands Lipopolysaccharides Liver Lung Mediator of activation protein Medical Methods Mus Nerve Neuropathy Nicotinic Receptors Organ Oxidative Stress Peritoneal Macrophages Pharmaceutical Preparations Physiological Plant Extracts Population Process Property Role Screening procedure Sum Telemetry Testing Therapeutic Tissues Vagus nerve structure Variant Wild Type Mouse alcohol abuse therapy alcohol effect alcohol exposure alcohol research alcoholism therapy alpha-bungarotoxin receptor base cell type cholinergic cost drug discovery in vivo macrophage neuronal cell body neuroprotection novel novel therapeutic intervention prevent receptor research study response restraint therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The tenth cranial nerve, the vagus, is distributed throughout the body, including major divisions to all parts of the gut, and to the liver. This cholinergic nerve restrains inflammation, in all the organs to which the vagus is distributed, by the tonic release of acetylcholine (ACh) onto nicotinic receptors (nicAChRs) of the alpha7- subtype. In addition to their presence on inflammatory cells, alpha7-nicAChRs are also present on cell bodies of the vagus in the CNS, where they cause vagal activation and neuroprotection. Since the presence of alcohol inhibits alpha7-nicAChRs, and a known chronic effect is to cause vagal neuropathy, these anti-inflammatory effects of the vagus are seriously compromised during alcohol exposure. The primary hypothesis is that this reduced vagal function contributes to the chronic inflammation following oxidative stress, which is a common feature of alcohol-induced damage in many organs. If correct, this predicts that compounds with alpha7- nicAChR agonist properties will protect against alcohol-induced tissue damage, particularly if these compounds are also anti-oxidants. The first specific aim of this proposal is to test the primary hypothesis in vitro by studying the interactions of alcohol and alpha7-nicAChR ligands on endotoxin-induced release of mediators from inflammatory cells (splenic, lung and peritoneal macrophages) from wild-type, and alpha7-nicAChR knock-out, C57Bl/6J mice. The second specific aim is to test the hypothesis in vivo by exposing C57Bl/6J mice (wild-type, vagotomized, and alpha7-nicAChR knockouts) chronically to alcohol by forced consumption, and then evaluating endotoxin-induced release of inflammatory mediators in vivo. As part of these studies we will evaluate the therapeutic potential of the alpha7-nicAChR agonist, choline, and a methylquercetagetin which acts as a partial agonist at alpha7-nicAChRs. The latter was recently discovered by screening a native plant extract library, and has potent anti-oxidant activity in addition to its action at nicAChRs, where it has an affinity comparable to choline. The ability of these compounds to inhibit endotoxin-induced release of inflammatory mediators following alcohol exposure will be studied in vitro and in vivo using the same methods as above. This project therefore tests a novel hypothesis for alcohol-induced organ damage based on the interaction between brain, gut and liver as represented by the vagus nerve, and tests a novel therapeutic approach to this. 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. Despite this there are currently no accepted approaches to preventing or reversing this damage. This application proposes a novel hypothesis as to the cause of organ damage which has profound implications for treatment. If successful, the project will establish a framework for drug discovery and evaluation in relation to this largely overlooked therapeutic target.

描述（由申请人提供）：第十脑神经，即迷走神经，分布于全身，包括肠道所有部分和肝脏的主要分支。这种胆碱能神经通过将乙酰胆碱（ACh）强直释放到α7-亚型的烟碱受体（nicAChR）上来抑制迷走神经分布的所有器官中的炎症。除了存在于炎症细胞上外，α7-nicAChR 还存在于中枢神经系统迷走神经细胞体上，引起迷走神经激活和神经保护。由于酒精的存在会抑制 α7-nicAChR，并且已知的慢性效应是导致迷走神经病变，因此迷走神经的这些抗炎作用在酒精暴露期间会受到严重损害。主要假设是，迷走神经功能的降低会导致氧化应激后的慢性炎症，这是酒精引起的许多器官损伤的一个共同特征。如果正确的话，这预示着具有 α7-nicAChR 激动剂特性的化合物将防止酒精引起的组织损伤，特别是如果这些化合物也是抗氧化剂的话。该提案的第一个具体目标是通过研究酒精和 α7-nicAChR 配体对内毒素诱导的野生型炎症细胞（脾、肺和腹膜巨噬细胞）介质释放的相互作用，在体外测试主要假设，以及α7-nicAChR 敲除，C57Bl/6J 小鼠。第二个具体目标是通过强制饮酒将 C57Bl/6J 小鼠（野生型、迷走神经切断型和 α7-nicAChR 敲除型）长期暴露于酒精中，然后评估内毒素诱导的体内炎症介质释放，从而在体内检验这一假设。作为这些研究的一部分，我们将评估 α7-nicAChR 激动剂、胆碱和甲基槲皮素（作为 α7-nicAChR 的部分激动剂）的治疗潜力。后者是最近通过筛选天然植物提取物文库发现的，除了对 nicAChR 的作用外，还具有有效的抗氧化活性，其亲和力与胆碱相当。将使用与上述相同的方法在体外和体内研究这些化合物在酒精暴露后抑制内毒素诱导的炎症介质释放的能力。因此，该项目基于以迷走神经为代表的大脑、肠道和肝脏之间的相互作用，测试了酒精引起的器官损伤的新假设，并测试了一种新的治疗方法。公共卫生相关性：酗酒（无论是依赖还是滥用）影响着超过 8% 的美国人口，每年造成的社会成本接近 2000 亿美元。其中大约一半是医疗费用，其中大部分用于治疗与酒精相关的器官损伤。尽管如此，目前还没有公认的方法来预防或扭转这种损害。该申请提出了关于器官损伤原因的新假设，这对治疗具有深远的影响。如果成功，该项目将建立一个与这一很大程度上被忽视的治疗目标相关的药物发现和评估框架。