REGIONAL BRAIN METABOLISM IN HEPATIC COMA

肝昏迷时的区域脑代谢

• 批准号: 3396853
• 负责人: RICHARD A HAWKINS
• 金额: $ 21.33万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3396853
• 关键词: GABA receptor; aminoacid biosynthesis; aminoacid transport; ammonia; autoradiography; blood brain barrier; brain metabolism; carbon dioxide fixation; cardiovascular shunt surgery; disease /disorder model; enzyme inhibitors; gamma aminobutyrate; glucose metabolism; glutamate ammonia ligase; glutamine; hepatectomy; hepatic coma /encephalopathy; high performance liquid chromatography; indoles; inhibitor /antagonist; laboratory rat; liver failure; neurotransmitter metabolism; nitrogen metabolism; p chlorophenylalanine

Liver failure and the associated brain malfunction is a major cause of morbidity and mortality in the United States, yet the etiology remains poorly understood. The encephalopathy associated with liver failure appears to be metabolic in origin and therefore potentially reversible. Therefore, knowledge of the mechanisms involved would enable the further development of sound therapeutic approaches: We recently found new evidence for the importance of ammonia in initiating a series of metabolic abnormalities characteristic of both chronic and acute hepatic encephalopathy, such as decreased brain glucose consumption, increased blood-brain barrier transport of neutral amino acids, and increased brain content of monoamine neurotransmitter precursor amino acids. Our experiments show that, contrary to previous opinion, ammonia itself is innocuous, and causes these abnormalities only on metabolism to glutamine. When glutamine synthetase is inhibited, the changes can largely be prevented or even reversed. We plan to investigate this in more detail, and to attempt to establish how glutamine synthesis leads to encephalopathy. We will study the effect of raised brain glutamine alone, inhibition of glutamine synthesis in established portalsystemic encephalopathy, the distribution of ammonia metabolism in brain, and the relationship with decreased glucose use and increased amino acid transport. Because GABA neurotransmission may be involved at a later stage in the chain of events leading to encephalopathy, we will study the effects of an antagonist of the benzodiazepine site on the GABA/A receptor, which has benefited some patients in hepatic coma. Acute or fulminant hepatic failure seems to share some characteristics of chronic liver disease with regard to its effects on cerebral function. To expand our knowledge from portalsystemic encephalopathy to fulminant hepatic encephalopathy, we will study models of acute liver failure. Our overall goal is to identify those common biochemical steps crucial to the development of encephalopathy in both acute and chronic liver failure.

肝衰竭和相关的脑功能障碍是导致肝衰竭的主要原因。 发病率和死亡率在美国，但病因仍然存在 不太了解。 肝衰竭相关脑病 似乎是代谢性的，因此可能是可逆的。 因此，了解所涉及的机制将有助于进一步 合理治疗方法的发展：我们最近发现了新的证据， 氨在引发一系列代谢过程中的重要性 慢性和急性肝脏异常特征 脑病，如脑葡萄糖消耗减少，增加 中性氨基酸的血脑屏障转运，并增加脑 单胺类神经递质前体氨基酸含量。 我们 实验表明，与以前的观点相反，氨本身是 无害，并导致这些异常仅对代谢谷氨酰胺。 当谷氨酰胺合成酶被抑制时，这些变化可以在很大程度上被抑制。 阻止甚至逆转。 我们计划对此进行更详细的调查， 并试图建立谷氨酰胺合成如何导致 脑病 我们将研究单独提高脑谷氨酰胺的作用， 谷氨酰胺合成抑制 脑内氨代谢的分布，以及 与葡萄糖使用减少和氨基酸转运增加的关系。 因为GABA神经传递可能参与在后期阶段， 一系列导致脑病的事件，我们将研究 GABA/A受体上苯二氮卓位点的拮抗剂， 使部分肝昏迷患者受益。 急性或暴发性肝病 失败似乎与慢性肝病的一些特征相同， 对大脑功能的影响。 扩展我们的知识， 门体脑病到暴发性肝性脑病，我们将 研究急性肝衰竭的模型。 我们的总体目标是确定那些 常见的生化步骤对脑病的发展至关重要， 急性和慢性肝衰竭。