CARNITINE-DEPENDENT METABOLISM AND AMMONIA TOXICITY

肝硬化是一种常见的疾病，其中肝脏灌注是 受损和实质细胞逐渐受损， 摧毁. 由于肝功能丧失，中枢神经系统严重紊乱 中枢神经系统（CNS）也发生（肝性脑病）。 现有治疗 局限性，长期预后差。 中枢神经系统的影响被认为是 代表大脑被通常被移除的化合物中毒 从血浆中分离出来 虽然许多化合物可能有助于 观察到脑病，有充分的证据表明，氨是一个主要的 毒素 S.格里索利亚等人最近报道， 对先前给予L-肉碱的小鼠有毒， 长链脂肪酸的载体。 保护机制尚不清楚。 左旋卡尼汀保护作用的生化基础研究 将集中在两个问题：（1）是否L-肉碱，在一个保护性的， 剂量，穿过血脑屏障的量足以说明 对氨中毒的影响 脑摄取指数（BUI） 将在大鼠中测定L-肉碱。 BUI将被修改 BUI的变化将与变化相关， 氨中毒，如果有的话。 这些研究将表明， 影响发生在外周或中枢神经系统内;相关研究将 阐明肉毒碱在脑内的代谢作用。 (2)是什么 肉毒碱改变氨毒性的机制？ 肉毒碱刺激 脂肪酸氧化，从而增加线粒体内乙酰辅酶A 合成，最终形成ATP。 增加ATP水平可以保护 中枢神经系统直接受到氨中毒或可能刺激肝尿素 形成并因此降低血浆氨水平。 通过刺激酮 身体形成肉毒碱也可以增加中枢神经系统的能量来源， 从而为谷氨酰胺合成保留葡萄糖碳。 替代地通过 刺激肌肉肉毒碱中支链氨基酸的使用可能会增加 谷氨酰胺形成并降低血浆氨水平。 这些假设 (and可能还有其他人）将在体外和体内研究， 有效和特异性的关键酶抑制剂所需的假设 肉毒碱效应 施用此类抑制剂应减少 肉毒碱的保护作用，如果阻断途径是重要的。 在先前的研究中已经开发了几种所需的抑制剂。 不相关的研究;其他在申请中提出。

Cirrhosis of the liver is a common disease in which hepatic perfusion is compromised and parenchymal cells are progressively damaged and eventually destroyed. As hepatic function is lost, severe derangements of the central nervous system (CNS) also occur (hepatic encephalopathy). Available therapies are limited, and the long-term prognosis is poor. The CNS effects are believed to represent an intoxication of the brain by compounds normally removed from plasma by the liver. Although many compounds may contribute to the observed encephalopathy, there is abundant evidence that ammonia is a major toxin. S. Grisolia et al. recently reported that ammonia is much less toxic to mice previously given L-carnitine, a mitochondrial transport carrier for long-chain fatty acids. The protective mechanism is unknown. Studies of the biochemical basis for the protective effect of L-carnitine will focus on two questions: (1) Does L-carnitine, given at a protective dose, cross the blood-brain barrier in amounts sufficient to account for its effect on ammonia toxicity? The brain uptake index (BUI) for L-carnitine will be determined in rats. The BUI will then be altered pharmacologically, and the changes in BUI will be correlated with changes in ammonia toxicity, if any. The studies will indicate if the carnitine effect occurs peripherally or within the CNS; related studies will elucidate the metabolic role of carnitine in brain. (2) What is the mechanism by which carnitine alters ammonia toxicity? Carnitine stimulates fatty acid oxidation and thus increases intramitochondrial acety-CoA synthesis and, ultimately, ATP formation. Increased ATP levels may protect the CNS from ammonia toxicity directly or may stimulate hepatic urea formation and thus decrease plasma ammonia levels. By stimulating ketone body formation carnitine could also increase CNS energy sources and may thereby spare glucose carbon for glutamine synthesis. Alternatively, by stimulating branched-chain amino acid use in muscle carnitine may increase glutamine formation and decrease plasma ammonia levels. These hypotheses (and possibly others) will be investigated in vitro and in vivo using potent and specific inhibitors of key enzymes required for the hypothesized carnitine effect. Administration of such inhibitors should diminish the protective effect of carnitine if the blocked pathway is important. Several of the required inhibitors have been developed in previous unrelated studies; others are proposed in the application.