KETOGENIC DIET AND BRAIN AMINO ACID METABOLISM

生酮饮食与大脑氨基酸代谢

基本信息

批准号：
6540016
负责人：
MARC YUDKOFF
金额：
$ 27.52万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-06-01 至 2004-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6540016
关键词：
acetoacetates age difference aminoacid metabolism brain metabolism diet therapy dietary lipid epilepsy gamma hydroxybutyrate glutamates ketone body laboratory rat milk nonhuman therapy evaluation nutrition related tag

项目摘要

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.

描述（来自申请人的摘要）生酮饮食通常用于对抗癫痫药物抗药性儿童的控制癫痫发作。这行动方式是完全未知的。 PI根据他们的初步数据，这是酮体的原因之一（3-OH丁酸和乙酸乙酸酯）在控制癫痫发作方面非常有效，以至于它们增加 GABA的脑浓度（伽马氨基丁酸），主要抑制性神经递质，并降低天冬氨酸的浓度兴奋性化合物。酮体带来了这些变化，因为它们急剧降低谷氨酸到天冬氨酸的跨度速度。作为结果，更多的谷氨酸可用于合成GABA。在星形胶质细胞，更多的谷氨酸可用于谷氨酰胺合成酶路径。这导致谷氨酰胺的合成增加，高度 GABA的有效前体。他们建议通过开发一个大鼠模型来检验这一假设生酮饮食。该模型涉及延长（从几周到几个月）用人造大鼠牛奶或等位基量喂食大鼠幼崽高脂量（生酮饮食）。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。质谱法被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。三个具体目的是：（1）检验上述假设；（2）至表征生酮饮食：需要高脂肪进食，或者可能酮体仅喂食吗？氨基酸变化的速度如何发展？如何他们持续吗？在不太成熟的动物中，变化更明显吗？（3）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，以及这种治疗作用是否为与模仿其中的氨基酸水平的变化有关控制动物。