DIAZEPAM BINDING INHIBITOR IN HEPATIC ENCEPHALOPATHY

安定结合抑制物(DBI)在肝纤维化发病机制中的作用 脑病将在人类和动物身上进行研究。最新的关于 肝性脑病的神经化学病因学提示 抑制性神经递质GABA系统的激活。GABA受体 已知的是，苯二氮卓类药物对这些位点有调节作用。此外，肝脏 动物和人类的脑病可以通过以下方法得到改善 苯二氮类拮抗剂的给药。神经肽DBI是一种 苯二氮卓类BABA系统的内源性变构调节剂 受体。这些实验将在动物和人类身上检验 DBI代谢在肝性脑病中的改变及其变化 与脑病临床指标相关。在预赛中 实验发现，脑脊液DBI在 肝性脑病患者，在非脑病患者中正常 患有肝病的患者。提议的实验的一个主要目标 将定量测定肝病患者和非肝病患者脑脊液中的DBI 肝性脑病及其与其他临床的关系 异常现象。由于从人类获取数据是有限的，一个主要目标是 这项建议将是利用和分析动物模型的 脑病。中枢神经系统DBI将在各种情况下进行量化 急、慢性肝性脑病动物模型及动物模型 非肝性脑病模型。计划进行实验，以量化 不同脑区DBI的mRNA含量增加 对其合成的理解。此外，为了检验假设， DBI或其代谢产物可能导致肝性脑病， 神经肽将被注射到动物的中枢神经系统。最后， 苯二氮卓类拮抗剂逆转的有效性和特异性 将在建议的系列中检查肝性脑病 实验。对DBI在肝病发病机制中作用的认识 脑病可能导致重要的药物治疗。 疾病。

The role of diazepam-binding inhibitor (DBI) in the pathogenesis of hepatic encephalopathy will be studied in humans and animals. Recent theories on the neurochemical etiology for hepatic encephalopathy have suggested activation of inhibitory neurotransmitter GABA systems. GABA receptor sites are known to be modulated by benzodiazepines. Furthermore, hepatic encephalopathy can be ameliorated in animals and humans by the administration of benzodiazepine antagonists. The neuropeptide DBI is an endogenous allosteric modulator of BABA systems at the benezodiazepine receptor. These experiments will examine, in animals and humans, whether DBI metabolism is altered in hepatic encephalopathy and how these changes correlate with clinical indices of encephalopathy. In preliminary experiments cerebrospinal fluid DBI was found to be markedly elevated in patients with hepatic encephalopathy and was normal in non-encephalopathic patients with liver disease. A primary goal of the proposed experiments will be to quantify DBI in the CSF of patients with hepatic as well as non- hepatic encephalopathy and to correlate these changes with other clinical abnormalities. Since data acquisition from humans is limited, a major goal of this proposal will be the utilization and analysis of animal models of encephalopathy. Central nervous system DBI will be quantified in various animal models of acute and chronic hepatic encephalopathy as well as animal models of non-hepatic encephalopathy. Experiments are planned to quantify the content of mRNA for DBI in various brain regions to add the understanding of its synthesis. Furthermore, to test the hypothesis that DBI or its metabolites may be responsible for hepatic encephalopathy, the neuropeptide will be administered to the CNS of animals. Finally, the effectiveness and specificity of benzodiazepine antagonists in the reversal of hepatic encephalopathy will be examined in the proposed series of experiments. Understanding of role of DBI in the pathogenesis of hepatic encephalopathy may lead to important pharmacological therapies in this disease.