KETOGENIC DIET AND BRAIN AMINO ACID METABOLISM

说明（来自申请人的摘要）生酮饮食通常用于 控制对抗癫痫药物有抵抗力的儿童的癫痫发作。 的 作用方式完全未知。 PI假设，基于他们的 初步数据显示，酮体（3-OH-丁酸和 乙酰乙酸酯）在控制癫痫发作方面如此有效， 大脑中GABA（γ-氨基丁酸）的浓度， 抑制性神经递质，降低天冬氨酸的浓度， 兴奋性化合物 酮体带来这些变化，因为它们 显著降低谷氨酸转氨为天冬氨酸的速率。 作为 结果，更多的谷氨酸可用于GABA的合成。 在 星形胶质细胞，更多的谷氨酸可用于谷氨酰胺合成酶 通路 这导致谷氨酰胺的合成增加， GABA的有效前体 他们建议通过开发一种大鼠模型来验证这一假设。 生酮饮食 该模型涉及长期（从数周到数月） 用人工鼠乳或等热量的 高脂肪（生酮饮食）。 他们将使用稳定的同位素，例如， 15 N和13 C，以测量谷氨酸代谢为GABA、天冬氨酸和 谷氨酰胺。 质谱法用作分析工具， 测量氨基酸和三羧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） 生酮饮食的特点：高脂肪喂养是必要的，还是可以 单喂酮体？ 氨基酸的变化有多快？ 如何 他们坚持吗？ 在不太成熟的动物中变化更明显吗？ 和（3）为了确定生酮饮食是否可以改善癫痫发作， 癫痫的标准大鼠模型，以及这种治疗效果是否 与氨基酸水平的变化有关，这些变化模拟了 对照动物。

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.