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”，我们提供证据表明谷氨酸 - 谷氨酰胺周期通常是脑GABA合成的主要来源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招募替代前体，目的是维持GABA池。在这个项目（M. Yudkoff，pi）中，我们通过使用稳定的同位素（主要是15N和13C）来识别主要GABA前体，对此概念进行审查并衡量癫痫毛果皮模型中GABA合成的速率。我们将利用质量量化同位素丰度的光谱法。我们在先前的研究脑氨基酸代谢，我们现在寻求将方法应用于研究癫痫。我们的初步发现证实了谷氨酰胺变得相对突出的概念 Pilocarpine模型中的GABA前体，特别是在海马中。我们发现丙氨酸和亮氨酸成为-NH2组的两个重要供体，形成谷氨酸，脑脱羧酸盐产生加巴。我们进一步假设生酮饮食，我们以前已证明它可以增加非癫痫动物中的脑GABA合成，可能对所产生的大鼠产生类似的敬意作用通过毛果皮治疗癫痫。确实，这个项目的目标是了解是否开始这种饮食在给药之前，毛果碱甚至可能会注意或流产癫痫发生。