PATHOGENESIS OF HEPATIC COMA

肝昏迷的发病机制

• 批准号: 3225644
• 负责人: Arthur Joseph Cooper
• 金额: $ 22.09万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-01-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3225644
• 关键词: alpha ketoglutarate; aminoacid metabolism; aspartate; astrocytes; bioenergetics; biological transport; blood brain barrier; brain disorder diagnosis; brain metabolism; cellular pathology; central nervous system disorders; diabetes mellitus; disease /disorder model; enzyme inhibitors; fluorimetry; gamma aminobutyrate; gas chromatography; glutamyltransferase; hepatic coma /encephalopathy; hepatotoxin; hypoxia; ion exchange chromatography; laboratory mouse; laboratory rat; liver metabolism; malates; medical complication; neurochemistry; neurons; neurotoxins; neurotransmitter metabolism; nitrogen balance; oxygen consumption; protein metabolism; radionuclide diagnosis; radiotracer; spectrometry; tissue /cell culture

Ammonia is a major toxin in the CNS and interferes with cerebral energy metabolism. Ammonia may exert its deleterious effect by interfering with the transport of "reducing equivalents" between cytosol and mitochondria. With the use of a new inhibitor of aspartate aminotransferase, i.e. Beta-methyleneaspartate (BetaMA), we have shown that the malate-aspartate shuttle (MAS) operates in brain for the transport of reducing equivalents. The data strongly suggest that the MAS and tricarboxylic acid cycle are tightly linked. We wish to extend these studies to determine whether excess ammonia produces the same biochemical effects (e.g. decreased 02 consumption and decreased ATP) as does BetaMA, and to determine whether the effects are additive. The astrocytes in the brains of liver disease patients and in the brains of portacaval-shunted rats are morphologically abnormal (Alzheimer type II changes). This abnormality may be due to a greater susceptibility to ammonia-induced metabolic impairment in astrocytes than in neurons. To test this hypothesis, we will investigate the biochemical effects on cultures of neurons and astrocytes of acute and chronic exposure to excess ammonia and BetaMA. We will also use [13N]ammonia (13N, positron-emitter; t1/2=9.96 min) to determine to what extent normal metabolic compartmentation is disrupted in the hyperammonemic rat brain. The metabolism of 13N-labeled amino acids will be investigated in the brains of normal and hyperammonemic rats. Evidence will be sought that branched-chain amino acid mixtures exert their beneficial effects by acting to replenish small compartment (astrocytic) glutamate, thereby stimulating the MAS and improving the cerebral energy balance. With an understanding of a) how ammonia interferes with cerebral energy metabolism and b) how the brain attempts to maintain nitrogen homeostasis it may be possible to suggest improved therapeutic interventions in patients with liver disease.

氨是中枢神经系统中的一种主要毒素，干扰大脑能量 新陈代谢。氨可能会通过干扰 “还原当量”在细胞质和线粒体之间的运输。 通过使用一种新的天冬氨酸转氨酶抑制剂，即 β-亚甲基天冬氨酸(BetaMA)，我们已经证明了苹果酸-天冬氨酸 航天飞机(MAS)在大脑中运行，负责运输还原当量物质。 这些数据强烈地表明，MAS和三元酸循环是 紧密联系在一起。我们希望扩大这些研究，以确定是否 过量的氨会产生相同的生化效应(例如，减少的02 消费和降低的ATP)和BetaMA一样，并确定 效果是相加的。肝病患者脑内星形胶质细胞的研究 患者和门腔静脉分流大鼠脑内的形态结构 异常(阿尔茨海默病II型改变)。这种异常可能是由于 对氨性代谢损伤的易感性增加 星形胶质细胞多于神经元。为了验证这一假设，我们将调查 急性和慢性脑损伤对神经元和星形胶质细胞培养的生化影响 长期暴露在过量的氨和β-甲基丙烯酸甲酯中。我们还将使用 [13N]氨(13N，正电子发射体；T1/2=9.96分钟)以确定为什么 高氨血症患者正常代谢区划被破坏的程度 老鼠的大脑。将研究13N标记氨基酸的代谢。 在正常和高氨血症大鼠的大脑中。我们将寻找证据 支链氨基酸混合物通过以下方式发挥其有益作用 起补充小脑室(星形细胞)谷氨酸的作用，从而 刺激大脑中动脉，改善大脑能量平衡。带着一个 了解a)氨是如何干扰大脑能量代谢的 以及b)大脑试图维持氮素平衡的方式 有可能建议改善对慢性阻塞性肺疾病患者的治疗措施 肝病。