ENDOZEPINE 4--A NATURAL BENZODIAZEPINE RECEPTOR LIGAND

Endozepine-4是一种新发现的天然化学物质， 苯并二氮卓受体（endozepine），既不是苯并二氮卓受体， 肽。它是一种低分子量分子， 对于GABAA受体的苯二氮卓类结合位点， 在人类和大鼠大脑中的浓度与人体相关。它 选择性地作用于苯二氮卓受体。比如苯二氮 受体激动剂地西泮，它可以增强GABA介导的氯离子 通量，并可以作为抗惊厥药。此外，初步 研究提供证据表明，内皮素-4可引起脑病， 可能是特发性复发性木僵的原因， 肝性脑病拟议的研究将审查以下方面的作用： 内源性氮卓-4在特发性复发性木僵发病机制中的作用， 肝性脑病将使用动物模型来研究如何 人类和大鼠内氮卓-4引起脑病，以及这些作用是否 通过苯二氮卓受体发生。 (l)我们将确定内氮平-4的改变， 特发性复发性木僵和肝性脑病 这些变化是否与临床水平或时间进程相关 脑病研究血清和脑脊液中内皮素-4的意义 将有助于确定其在 特发性复发性昏迷和肝性脑病。 (2)我们建议检验内氮平-4的改变 存在于肝性脑病的动物模型中， 内皮素-4可引起脑病，因此有助于 疾病意义：过量内皮素-4的动物模型和动物模型 脑病模型将使我们能够直接测试假设， 内西平-4可引起或促成脑病。 (3)我们将检验内西平的行为作用- 4是通过苯二氮卓受体介导的， 和抗惊厥特性。重要性：这些研究将决定 如果天然存在的内卓-4具有其它内卓的功能性质 合成苯二氮激动剂-抗焦虑和/或抗惊厥药。 预计这些实验的结果将提供 关于一种新的神经调节剂的重要信息， 引起或促成某些脑病的。Endozepine-4可能 也是GABA能网络的重要变构调节剂， 神经系统此外，它可能作为一个新的 一类“天然”抗惊厥药物增加了对其研究的额外动力。

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.