ENDOZEPINE 4--A NATURAL BENZODIAZEPINE RECEPTOR LIGAND

内氮卓4--天然苯二氮卓受体配体

• 批准号: 2271470
• 负责人: Jeffrey D Rothstein
• 金额: $ 23.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2271470
• 关键词: anticonvulsants; benzodiazepine receptor; bicuculline; cerebrospinal fluid; disease /disorder model; electroencephalography; hepatic coma /encephalopathy; high performance liquid chromatography; human subject; laboratory rat; ligands; neuropharmacology; pentylenetetrazole; psychopharmacology; receptor binding; serum; tranquilizer

Endozepine-4 is a newly identified natural chemical that is active at the benzodiazepine receptor (endozepine), and is neither a benzodiazepine nor a peptide. It is a low molecular weight molecule that has a high affinity for the benzodiazepine binding site of the GABAA receptor and is present in pharmacologically relevant concentrations in human and rat brain. It acts selectively at the benzodiazepine receptor. Like the benzodiazepine receptor agonist, diazepam, it can potentiate GABA-mediated chloride fluxes, and can serve as an anticonvulsant. Furthermore, preliminary studies provide evidence that endozepine-4 can cause encephalopathy, and may be the cause of idiopathic recurring stupor and may contribute to hepatic encephalopathy. The proposed studies will examine the role of endozepine-4 in the pathogenesis of idiopathic recurring stupor and hepatic encephalopathy. An animal model will be used to investigate how human and rat endozepine-4 causes encephalopathy and whether these actions occur via the benzodiazepine receptor. (l) We will identify alterations in endozepine-4 in patients with idiopathic recurring stupor and hepatic encephalopathy and determine whether these changes correlate with the clinical level or temporal course of encephalopathy. Significance: Studying endozepine-4 in serum and CSF from patients with these disorders will serve to define its role in idiopathic recurring stupor and hepatic encephalopathy. (2) We propose to test the hypothesis that alterations of endozepine-4 exist in animal models of hepatic encephalopathy and that excess endozepine-4 can cause encephalopathy and therefore contribute to the disease. Significance: Animal models of excess endozepine-4 and animal encephalopathy models will allow us to directly test the hypothesis that endozepine-4 can cause or contribute to encephalopathy. (3) We will test the hypothesis that the behavioral actions of endozepine- 4 are mediated via benzodiazepine receptors by examining its anti-anxiety and anti-convulsant properties. Significance: These studies will determine if naturally occurring endozepine-4 has the functional properties of other synthetic benzodiazepine agonists - anxiolytic and/or anticonvulsant. It is anticipated that the results of these experiments should provide important information on a new neuromodulator that may be an important cause or contributor to certain encephalopathic diseases. Endozepine-4 may also be an important allosteric regulator of GABAergic networks in the nervous system. In addition, the possibility that it could serve as a new class of "natural" anticonvulsants adds additional impetus for its study.

恩多西平-4是一种新发现的天然化学物质，活性在 苯二氮卓类受体(Endzepine)，既不是苯二氮卓类，也不是 一种多肽。它是一种具有高亲和力的低分子分子。 用于GABAA受体的苯二氮卓类结合部位，并存在 在人和大鼠脑内的药理上相关的浓度。它 选择性地作用于苯二氮卓类受体。就像苯二氮类药物 受体激动剂安定，它可以增强GABA介导的氯离子 助熔剂，并可用作抗惊厥药。此外，初步的 研究提供证据表明，内皮西平-4可以导致脑病， 可能是特发性复发性昏迷的原因，并可能导致 肝性脑病。拟议的研究将审查 Endozepine-4在特发性复发性昏迷和癫痫发病机制中的作用 肝性脑病。一个动物模型将被用来研究 人和大鼠内皮西平-4导致脑病以及这些作用 通过苯二氮卓类受体发生。 (L)我们将确定慢性阻塞性肺疾病患者内源性齐平-4的变化 特发性复发性昏迷和肝性脑病的诊断 这些变化是否与临床水平或时间病程相关 脑病的症状。研究血清和脑脊液中内皮质酮-4的意义 来自这些疾病患者的将有助于确定它在 特发性复发性昏迷和肝性脑病。 (2)我们建议检验这样一种假设，即内皮齐平-4的变化 存在于肝性脑病的动物模型中 Endozepine-4可导致脑病，从而导致 疾病。意义：过量内分泌-4的动物模型和动物 脑病模型将允许我们直接测试假设 Endozepine-4可引起脑病或导致脑病。 (3)我们将检验这样一种假设，即内达西平的行为作用- 4通过检测其抗焦虑作用通过苯二氮卓类受体介导。 和抗惊厥特性。意义：这些研究将确定 如果自然产生的内皮西平-4具有其他 合成苯二氮卓类激动剂--抗焦虑和/或抗惊厥药。 预计这些实验的结果应该会提供 关于一种新的神经调节剂的重要信息，可能是一种重要的 导致或促成某些脑部疾病。恩多西平-4可能 也是GABA能网络中重要的变构调节器 神经系统。此外，它可能会成为一种新的 一类“天然”的抗惊厥药物为其研究增添了额外的动力。