HEPATIC COMA--GLIAL BENZODIAZEPINE RECEPTORS & STEROIDS

肝昏迷--神经胶质苯二氮卓受体

• 批准号: 2750929
• 负责人: MICHAEL David NORENBERG
• 金额: $ 14.04万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-15 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750929
• 关键词: ammonia; astrocytes; benzodiazepine receptor; benzodiazepines; glia; hepatic coma /encephalopathy; high performance liquid chromatography; immunocytochemistry; laboratory rat; neurotransmitters; steroids

DESCRIPTION (Adapted from Applicant's Abstract): The investigator proposes, in this revised competitive renewal, to study the pathogenic mechanisms of hepatic encephalopathy. The mechanism which lead to hepatic encephalopathy are not well understood but in recent years there has been substantial evidence which implicates ammonia, astrocytes, and excessive GABAergic activity mediated by elevated levels of endogenous benzodiazepines. During the prior funding period, the investigator studied the role of astrocytes, ammonia and benzodiazepines in hepatic encephalopathy and in their prior studies they found that 1) ammonia upregulates the peripheral benzodiazepine receptor in cultured astrocytes an in animal models of hepatic encephalopathy and 2) peripheral benzodiazepine receptor (PBR) blockers ameliorate ammonia toxicity in vivo. They also found that neurosteroids (which are products of PBR activation) are elevated in animal models of hepatic encephalopathy and in ammonia treated astrocyte cultures, and that some of these neurosteroids exert behavioral and neuropathologic changes similar to hepatic encephalopathy. Their hypothesis is that neurosteroids that positively modulate the GABAA receptor contribute to the pathogenesis of HE. They further propose that the elevation of neurosteroids result from an upregulation of astrocytic PBR by the hyperammonemia associated with liver failure. To test the hypothesis, they plan to investigate the profile of neurosteroids in animal models of HE and ammonia treated astrocyte cultures. They plan to determine whether neurosteroids are elevated in HE and are able to reproduce the clinical, pathological, and neurochemical features of HE. They will also examine whether inhibiting the synthesis or action of neurosteroids that have a positive modulatory effect on the GABAA receptor will improve the outcome of the experimental HE. They plan to study the role of astrocytic PBRs in the generation of neurosteroids from brains of animal models of HE by investigating PBR binding parameters. Measuring PBR mRNA steady-state levels, and localizing changes in the PBR by in situ hybridization. The functional integrity of the PBR will be examined by measuring the rate of pregnenolone synthesis. To establish the role of ammonia in the PBR-dependent production of neurosteroids by astrocytes, similar studies will be carried out in cultured astrocytes. Their proposed mechanism, whereby ammonia upregulates the astrocytic PBR resulting in elevated levels of neurosteroids that act on the neuronal GABAA receptor synthesizes current pathogenic views and more importantly, provides the potential for novel therapeutic approaches through intervention of neurosteroid effects.

描述(改编自申请人摘要)：调查人员提出， 在这次修订的竞争更新中，研究致病机制 肝性脑病。肝性脑病的发病机制 没有被很好地理解，但近年来有大量的 有证据表明氨、星形胶质细胞和过量的GABA能 内源性苯二氮卓类药物水平升高所介导的活性。在.期间 在之前的资助期间，研究人员研究了星形胶质细胞的作用， 氨水和苯二氮卓类药物在肝性脑病及其先证者中的应用 研究发现，1)氨会上调外周的苯二氮卓类药物 培养的星形胶质细胞受体在肝损伤动物模型中的表达 脑病和2)外周苯二氮卓受体(PBR)阻滞剂 改善体内氨毒性。他们还发现，神经类固醇 (它们是PBR激活的产物)在动物模型中升高 肝性脑病和氨处理的星形胶质细胞培养中， 其中一些神经类固醇会引起行为和神经病理改变。 类似于肝性脑病。他们的假设是神经类固醇 正向调节GABAA受体参与发病机制 他的名字。他们进一步提出，神经类固醇的升高是由 高氨血症引起的星形胶质细胞PBR上调 肝功能衰竭。为了验证这一假设，他们计划调查这一侧写 神经类固醇在HE和氨水处理的星形胶质细胞模型中的表达 文化。他们计划确定高血压患者的神经类固醇水平是否升高 并且能够复制临床、病理和神经化学物质 他的特征。他们还将检查是否抑制合成或 对GABAA有正向调节作用的神经类固醇作用 受体可改善实验性肝性脑病的预后。他们计划 星形胶质细胞PBRs在神经类固醇生成中的作用研究 通过研究PBR结合参数来研究HE动物模型的脑组织。 测量PBR mRNA的稳态水平，并通过以下方式定位PBR的变化 原位杂交。将检查PBR的功能完整性 通过测量孕烯醇酮的合成速率。确立…的角色 星形胶质细胞依赖PBR产生神经类固醇的氨， 类似的研究将在培养的星形胶质细胞中进行。他们的建议 氨上调星形细胞PBR导致 作用于神经元GABAA受体的神经类固醇水平升高 综合了当前的致病观点，更重要的是，提供了 通过介入治疗来开发新的治疗方法的潜力 神经类固醇效应。