KETOGENIC DIET AND BRAIN AMINO ACID METABOLISM

生酮饮食与大脑氨基酸代谢

• 批准号: 6187848
• 负责人: MARC YUDKOFF
• 金额: $ 26.12万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187848
• 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

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 控制对抗癫痫药物有抵抗力的儿童的癫痫发作。 这 作用方式完全未知。 PI 根据他们的假设 初步数据表明，酮体（3-OH-丁酸酯和 乙酰乙酸盐）在控制癫痫发作方面如此有效，因为它们会增加 GABA（γ 氨基丁酸）的大脑浓度，这是一种主要的 抑制性神经递质，并降低天冬氨酸的浓度， 兴奋性化合物。 酮体带来这些变化是因为它们 急剧降低谷氨酸转氨为天冬氨酸的速率。 作为一个 结果，更多的谷氨酸可用于合成 GABA。 在 星形胶质细胞，谷氨酰胺合成酶可以利用更多的谷氨酸 途径。 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。 他们建议通过开发大鼠模型来检验这一假设 生酮饮食。 该模型涉及长期（从几周到几个月） 用人造大鼠奶或等热量喂养幼鼠 高脂肪量（生酮饮食）。 他们将使用稳定同位素，例如 15N 和 13C 用于测量谷氨酸代谢为 GABA、天冬氨酸和 谷氨酰胺。 质谱法被用作一种分析工具，可用于 测量氨基酸和三羧酸中的稳定同位素丰度 循环中间体。 三个具体目标是：（1）检验上述假设； (2) 至 描述生酮饮食的特征：是否需要高脂肪喂养，或者可以 单独喂酮体可以吗？ 氨基酸变化发生的速度有多快？ 如何 他们持续吗？ 较不成熟的动物的变化是否更明显？ (3) 确定生酮饮食是否可以改善癫痫发作 标准大鼠癫痫模型，以及这种治疗效果是否有效 与模拟氨基酸水平的变化相关 控制动物。