PATHOGENESIS OF HEPATIC COMA

肝昏迷的发病机制

• 批准号: 3225646
• 负责人: Arthur Joseph Cooper
• 金额: $ 25.1万
• 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 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3225646
• 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主要毒素，并干扰大脑能量 新陈代谢. 氨可能通过干扰 细胞质和线粒体之间的“还原当量”运输。 使用新的天冬氨酸转氨酶抑制剂，即 β-亚甲基天冬氨酸（BetaMA），我们已经表明，苹果酸-天冬氨酸 穿梭机（MAS）在脑中运行，用于运输还原当量。 这些数据有力地表明，MAS和三羧酸循环是 紧密相连。 我们希望扩大这些研究，以确定是否 过量的氨产生相同的生物化学效应（例如 消耗和ATP减少），如BetaMA，并确定是否 效果是叠加的。 肝病患者脑内的星形胶质细胞 患者和门腔静脉分流大鼠的大脑中的形态学 异常（阿尔茨海默病II型改变）。 这种异常可能是由于 对氨诱导的代谢障碍更敏感， 而不是神经元。 为了验证这一假设，我们将调查 急性和急性脑缺血对神经元和星形胶质细胞培养的生化影响 长期暴露于过量的氨和β-甲基苯丙胺 我们还将使用 [13 N]氨（13 N，正电子发射体; t1/2=9.96 min），以确定 在高氨血症患者中，正常代谢区室化被破坏的程度 老鼠的大脑 将研究13 N标记的氨基酸的代谢 在正常和高氨血症大鼠的大脑中。 我们会寻找证据 支链氨基酸混合物通过以下方式发挥其有益效果： 作用于补充小隔室（星形胶质细胞）谷氨酸，从而 刺激MAS并改善大脑能量平衡。 与 理解a）氨如何干扰大脑能量代谢 以及B）大脑如何试图维持氮稳态， 可能建议改善患者的治疗干预措施， 肝脏疾病