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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：
8334496
负责人：
JOHN M. LITTLETON
金额：
$ 19.98万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334496
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.

描述（由申请人提供）：第十脑神经，迷走神经，分布于全身，包括通往肠道各部分和肝脏的主要分支。这种胆碱能神经通过向α 7-亚型的烟碱受体（nicachr）强直性释放乙酰胆碱（ACh）来抑制迷走神经分布的所有器官的炎症。除了存在于炎症细胞上，alpha7- nicachr也存在于中枢神经系统的迷走神经细胞体上，在那里它们引起迷走神经激活和神经保护。由于酒精的存在抑制了α 7- nicachr，并且已知的慢性效应是引起迷走神经病变，因此在酒精暴露期间，迷走神经的这些抗炎作用严重受损。主要的假设是，这种迷走神经功能的降低导致了氧化应激后的慢性炎症，这是许多器官中酒精诱导损伤的共同特征。如果正确的话，这预示着具有α 7- 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。本提案的第一个具体目的是通过研究酒精和alpha7-nicAChR配体对内毒素诱导的炎症细胞（脾、肺和腹膜巨噬细胞）释放介质的相互作用，在体外验证主要假设，这些炎症细胞来自野生型和alpha7-nicAChR敲除的C57Bl/6J小鼠。第二个具体目的是通过强迫C57Bl/6J小鼠（野生型、迷走神经缺失型和alpha7-nicAChR敲除型）长期暴露于酒精中，在体内验证这一假设，然后评估内毒素诱导的炎症介质的体内释放。作为这些研究的一部分，我们将评估alpha7-nicAChR激动剂、胆碱和甲基槲皮素的治疗潜力，甲基槲皮素作为alpha7-nicAChR的部分激动剂。后者是最近通过筛选本地植物提取物文库发现的，除了在nicachr上的作用外，还具有强大的抗氧化活性，其亲和力与胆碱相当。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将在体外和体内使用与上述相同的方法进行研究。因此，该项目基于迷走神经所代表的大脑、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。