The Synthesis of GABA in Epileptic Brain

癫痫脑中 GABA 的合成

基本信息

批准号：
7251011
负责人：
MARC YUDKOFF
金额：
$ 23.62万
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：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251011
关键词：
Affect Alanine Alanine Transaminase Amino Acids Animal Model Animals Antiepileptic Agents Aspartate Astrocytes Blood Brain Caloric Restriction Collaborations Data Development Diet Dietary Intervention Disruption Enzymes Epilepsy Epileptogenesis Event Gene Targeting Genetic Glutamate Metabolism Pathway Glutamate-Ammonia Ligase Glutamates Glutamine Goals Hippocampus (Brain)In Vitro Injury Investigation Keto Acids Ketoses Ketosis Laboratories Learning Leucine Mass Spectrum Analysis Measures Metabolic Metabolism Methodology Modeling Neurons Pathway interactions Pattern Peripheral Pilocarpine Process Production Purpose Rate Rattus Recruitment Activity Recycling Regulation Research Research Personnel Role Source Therapeutic Therapeutic Intervention branched-chain-amino-acid transaminase concept experience gamma-Aminobutyric Acid in vivo ketogenic diet oxidation prevent programs research study restoration stable isotope transamination

项目摘要

This project is the "metabolic counterpart" to Project 1 (D. Coulter, PI), where we present evidence that the Glutamate-Glutamine Cycle, ordinarily the major source for brain GABA synthesis, does not subserve this crucial role with a similar intensity in epileptic brain. We hypothesize that in epilepsy the brain recruits alternate precursors for the purpose of maintaining pools of GABA. In this project (M. Yudkoff, PI), we scrutinize this concept by using stable isotopes (primarily 15N and 13C) to identify major GABA precursors and to measure rates of GABA synthesis in the pilocarpine model of epilepsy. We will utilize mass spectrometry to quantify isotopic abundance. We have made productive use of this approach in our prior investigations of brain amino acid metabolism, and we seek now to apply the methodology to the study of epilepsy. Our preliminary findings confirm the concept that glutamine becomes a relatively less prominent GABA precursor in the pilocarpine model, particularly in the hippocampus. We find that alanine and leucine become two important donors of -NH2 groups to form the glutamate that the brain decarboxylates to yield GABA. We further hypothesize that the ketogenic diet, which we have previously demonstrated to increase brain GABA synthesis in non-epileptic animals, might have a similarly salutary effect in rats rendered epileptic by pilocarpine treatment. Indeed, a goal of this project will be to learn whether initiation of this diet prior to administration of pilocarpine might even attentuate or abort epileptogenesis.

该项目是项目 1（D. Coulter，PI）的“代谢对应物”，我们在该项目中提供的证据表明谷氨酸-谷氨酰胺循环通常是大脑 GABA 合成的主要来源，但并不支持这一点在癫痫大脑中具有相似强度的关键作用。我们假设，在癫痫病中，大脑会招募用于维持 GABA 库的替代前体。在这个项目（M. Yudkoff，PI）中，我们通过使用稳定同位素（主要是 15N 和 13C）来仔细研究这一概念，以识别主要的 GABA 前体并测量毛果芸香碱癫痫模型中 GABA 的合成率。我们将利用质量光谱测定法来量化同位素丰度。我们在之前的研究中已经有效地利用了这种方法脑氨基酸代谢的研究，我们现在寻求将该方法应用于研究癫痫。我们的初步研究结果证实了谷氨酰胺变得相对不那么重要的概念。毛果芸香碱模型中的 GABA 前体，特别是在海马体中。我们发现丙氨酸和亮氨酸成为 -NH2 基团的两个重要供体，形成大脑脱羧产生的谷氨酸伽马氨基丁酸。我们进一步假设，我们之前已经证明生酮饮食可以增加非癫痫动物大脑 GABA 合成可能对大鼠产生类似的有益作用癫痫可采用毛果芸香碱治疗。事实上，该项目的一个目标是了解是否开始这种饮食在给予毛果芸香碱之前服用甚至可能减弱或中止癫痫发生。