DIAZEPAM BINDING INHIBITOR IN HEPATIC ENCEPHALOPATHY

地西泮结合抑制剂在肝硬化发病中的作用 脑病将在人类和动物中进行研究。 最近的理论 肝性脑病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 已知这些位点可被苯并二氮杂调节。 此外，肝 在动物和人类中， 苯二氮卓拮抗剂的给药。 神经肽DBI是一种 苯并二氮杂卓的BABA系统的内源性变构调节剂 受体的 这些实验将在动物和人类身上检验， DBI代谢在肝性脑病中发生改变，以及这些变化是如何发生的 与脑病的临床指标相关。 初步 实验脑脊液DBI被发现显着升高 肝性脑病患者，非脑病患者正常 肝病患者。 拟议实验的一个主要目标 将定量肝和非肝性脑梗死患者CSF中的DBI， 肝性脑病，并将这些变化与其他临床 异常 由于从人类获取的数据有限， 这一建议将是利用和分析的动物模型， 脑病 中枢神经系统DBI将在不同的 急性和慢性肝性脑病动物模型以及动物 非肝性脑病模型。 实验计划量化 DBI在不同脑区的mRNA含量，以增加 理解它的合成。 此外，为了验证假设， DBI或其代谢产物可能导致肝性脑病， 将神经肽施用至动物的CNS。 最后 苯二氮卓类拮抗剂在逆转 肝性脑病将在拟议的系列检查， 实验 DBI在肝硬化发病机制中的作用 脑病可能会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.