HUMAN CEREBRAL GABA METABOLISM STUDIED IN VIVO WITH NMR

描述(研究人员摘要)：谷氨酸是主要的 兴奋性和γ-氨基丁酸(GABA)是主要的抑制物 哺乳动物大脑和人类大脑皮质中的神经递质。动物模型 癫痫的症状一直表明GABA的突触功能 癫痫发作状态减少。对动物的广泛研究表明 GABA释放和新陈代谢的变化可能在 在缉获活动的起源和传播中发挥的作用。尽管它可以是 推论报告的临床益处在治疗 癫痫与脑部抬高有关并可归因于此 GABA，显示人类大脑GABA水平变化的证据是 缺乏。核磁共振波谱学的最新进展 (NMRS)允许对大脑进行第一次非侵入性测量 动物和人体内的GABA。大豆杉体内GABA合成和分解代谢的研究 人类大脑皮层将进一步了解这一重要的抑制作用 神经递质与人类健康和疾病。我们建议研究 非癫痫患者脑组织γ-氨基丁酸和谷氨酸水平的变化 志愿者和癫痫患者。维甲菊酯(Y-乙烯-Y-氨基 丁酸)，一种GABA转氨酶抑制剂，是最多的 前景看好的抗癫痫新药正在开发中。我们建议 慢性阻塞性肺疾病患者脑组织中γ-氨基丁酸和谷氨酸水平的变化 Vigabatrin给药剂量和时间对癫痫的影响 使用NlVlRS。这项研究有四个目标：在体内测量大脑 非癫痫和癫痫受试者的GABA和谷氨酸水平 癫痫患者脑组织γ-氨基丁酸水平测定 标准剂量和大剂量Vigabatrin测定脑内GABA 癫痫患者治疗前后的血药浓度变化 Vigabatrin治疗，比较GABA蓄积率 单次服药后GABA周转率的变化 长期给药前后大鼠模型的实验研究 使用13C标记的葡萄糖。

DESCRIPTION (Investigator's Abstract): Glutamate is the major excitatory and y-aminobutyric acid (GABA) the major inhibitory neurotransmitter in mammalian brain and human cortex. Animal models of epilepsy consistently indicate that GABA synaptic function is decreased in seizure states. Extensive studies in animals have shown that changes in GABA release and metabolism may play an important role in the origin and spread of seizure activity. Although it can be inferred that the clinical benefit reported in the treatment of epilepsy is associated with and attributable to elevation of brain GABA, evidence to show changes in brain GABA levels in man is lacking. Recent advances in nuclear magnetic resonance spectroscopy (NMRS) have permitted the first non-invasive measurements of cerebral GABA in animals and man. Studies of GABA synthesis and catabolism in human cortex will further understanding of this important inhibitory neurotransmitter in human health and disease. We propose to study changes in cerebral GABA and glutamate levels in non-epileptic volunteers and patients with epilepsy. Vigabatrin (y-vinyl-y-amino butyric acid), a GABA- transaminase inhibitor, is one of the most promising new anti-epileptic drugs under development. We propose to study changes in cerebral GABA and glutamate levels in patients with epilepsy as a function of dose and time of vigabatrin administration using NlVlRS. The study has four goals: To measure in vivo cerebral GABA and glutamate levels in non-epileptic and epileptic subjects, to measure cerebral GABA levels in epileptic subjects treated with standard dose and high dose vigabatrin, to measure cerebral GABA levels of epileptic subjects before and after initiation of vigabatrin therapy, and to compare the rate of GABA accumulation following a single dose of vigabatrin with the rate of GABA turnover before and after chronic administration of vigabatrin in a rat model using 13C-labeled glucose.