REGIONAL BRAIN METABOLISM IN HEPATIC COMA

肝功能衰竭和相关的大脑功能障碍是导致 美国的发病率和死亡率，但病因仍然存在 人们对此知之甚少。与肝功能衰竭相关的脑病 似乎是新陈代谢的起源，因此可能是可逆的。 因此，对所涉机制的了解将使 完善治疗方法的发展：我们最近发现了新的证据 氨在启动一系列新陈代谢中的重要性 慢性和急性肝病的特征异常 脑病，如大脑葡萄糖消耗减少，增加 血脑屏障转运中性氨基酸，增加脑组织 单胺类神经递质前体氨基酸含量。我们的 实验表明，与之前的观点相反，氨本身是 无毒，只对谷氨酰胺代谢造成这些异常。 当谷氨酰胺合成酶被抑制时，这种变化在很大程度上可以 阻止，甚至逆转。我们计划对此进行更详细的调查， 并试图确定谷氨酰胺合成是如何导致 脑病。我们将单独研究升高的大脑谷氨酰胺的影响， 门静脉系统谷氨酰胺合成的抑制作用 脑病，脑内氨代谢的分布，以及 与葡萄糖使用量的减少和氨基酸转运的增加有关。 因为GABA神经传递可能在以后的阶段参与 导致脑病的一连串事件，我们将研究 GABA/A受体上的苯二氮卓类部位的拮抗剂，它具有 使部分肝昏迷患者受益。急性或暴发性肝 肝功能衰竭似乎与慢性肝病的某些特征相同 关于它对大脑功能的影响。从……扩展我们的知识 门脉系统脑病到暴发性肝性脑病，我们将 研究急性肝功能衰竭模型。我们的总体目标是找出 常见的生化步骤对脑病的发展至关重要 包括急性和慢性肝功能衰竭。

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.