KETOGENIC DIET AND BRAIN AMINO ACID METABOLISM

说明(摘自申请者的摘要)生酮饮食通常用于 控制对抗癫痫药物有耐药性的儿童的癫痫发作。这个 行动模式完全未知。圆周率假设，基于他们的 初步数据表明，酮体(3-羟基丁酸酯和 乙酰乙酸乙酯)在控制癫痫发作方面是如此有效，因为它们增加了 大脑中GABA(伽马氨基丁酸)的浓度是一种主要的 抑制神经递质，降低天冬氨酸浓度 兴奋性化合物。酮体之所以带来这些变化，是因为它们 大幅降低谷氨酸转氨率为天冬氨酸。作为一名 结果更多的谷氨酸可用于合成GABA。在……里面 星形胶质细胞，谷氨酰胺合成酶可以获得更多的谷氨酸 路径。这导致谷氨酰胺的合成增加，谷氨酰胺是一种高度 GABA的有效前体。 他们建议通过建立大鼠模型来检验这一假说。 生酮饮食。该模式涉及到长时间(从几周到几个月) 用人造鼠奶或等卡路里饲料喂养小鼠 高脂肪(生酮饮食)的量。他们将使用稳定的同位素，例如， 15N和13C以测量谷氨酸代谢对GABA、天冬氨酸和 谷氨酰胺。质谱学被用作分析工具，用来 测定氨基酸和三元酸的稳定同位素丰度 循环中间体。 三个具体目标是：(1)检验上述假设；(2) 描述生酮饮食：高脂肪喂养是否必要，或可能 只有酮体才能被喂食吗？氨基酸变化的发展速度有多快？多么 他们坚持了吗？在不成熟的动物身上，变化会更明显吗？ 以及(3)确定生酮饮食是否可以改善癫痫发作。 标准的癫痫大鼠模型，以及这种治疗效果是否 与氨基酸水平的变化相关联，这种变化与 控制动物。

DESCRIPTION (from applicant's abstract) The ketogenic diet is often used to control seizures in children who are resistant to antiepileptic drugs. The mode of action is totally unknown. The PI hypothesizes, based on their preliminary data, that one reason the ketone bodies (3-OH-butyrate and acetoacetate) are so effective in controlling seizures is that they increase the brain concentration of GABA (gamma amino butyric acid), a major inhibitory neurotransmitter, and lower the concentration of aspartate, an excitatory compound. Ketone bodies bring about these changes because they sharply reduce the rate of transamination of glutamate to aspartate. As a result, more glutamate becomes available for the synthesis of GABA. In astrocytes, more glutamate becomes available to the glutamine synthetase pathway. This results in increased synthesis of glutamine, a highly effective precursor to GABA. They propose to test this hypothesis by developing a rat model of the ketogenic diet. The model involves the prolonged (from weeks to months) feeding of rat pups with either an artificial rat milk or an isocaloric amount of a high fat (ketogenic diet). They will use stable isotopes, e.g., 15N and 13C to measure rates of glutamate metabolism to GABA, aspartate and glutamine. Mass spectrometry is used as an analytical tool with which to measure stable isotopic abundance in amino acids and tricarboxylic acid cycle intermediates. The three specific aims are: (1) To test the above hypothesis; (2) To characterize the ketogenic diet: Is high fat feeding necessary, or could ketone bodies alone be fed? How rapidly do amino acid changes develop? How sustained are they? Are changes more pronounced in less mature animals?; and (3) To determine whether the ketogenic diet can ameliorate seizures in a standard rat model of epilepsy, and whether this therapeutic effect is associated with changes of amino acid levels that mimic those noted in control animals.