HUMAN CEREBRAL GABA METABOLISM STUDIED IN VIVO WITH NMR

说明(申请人摘要)：γ-氨基丁酸(GABA)是 主要抑制性神经递质在人脑皮质中起着关键作用 在抑制癫痫活动的起源和传播方面。核磁 共振光谱(NMRS)允许连续、非侵入性的代谢物和 对大多数人来说，没有不适或已知危险的高分子测量 人民。癫痫患者脑脊液和组织中GABA浓度降低 与频繁的癫痫发作有关。低GABA水平是不是 频繁发作的原因或结果尚不清楚。的有效性。 针对GABA代谢的一类抗癫痫药物，例如， Vigabitrin、Gabapentin、Tiagabine依赖于GABA的升高 集中精神。这项提案的重点是对GABA和 癫痫患者的同型卡那斯汀浓度。三个目标提出 前瞻性检测枕叶GABA和高卡那津的变化 由维卡他汀、加巴喷丁和替加他滨诱导。目的是为了提高 基于GABA和同型肌肽的AED筛选指南 级别。这些NMRS测量可能提供一种合理的方法 选择合适的药物。这项提议是第一次尝试 提供对大脑GABA和同型肌肽的“治疗水平”的估计， 类似于临床广泛使用的血清AED水平。第四个目标 建议前瞻性地检查颞叶切除术是否改变 枕叶GABA和同型肌肽浓度。答案可能会影响到 无论是病人的选择还是术后的长期管理。在 在过去的十年里，磁共振方法已经成为患者的标准护理方法 人类癫痫的评估。基于NMRS的神经递质测量 而调节剂应该在未来十年进入临床医疗机构。 这项提议将推进癫痫障碍的临床护理。

DESCRIPTION (Applicant's abstract): Gamma-amimo-butyric acid (GABA) is the major inhibitory neurotransmitter in human cortex and plays a pivotal role in suppressing the origin and spread of seizure activity. Nuclear magnetic resonance spectroscopy (NMRS) permits serial, non-invasive metabolite and macromolecule measurements without discomfort or known hazard for most people. Low CSF and tissue GABA concentrations in patients with epilepsy are associated with frequent seizures. Whether low GABA levels are the cause or the result of frequent seizures is unknown. The effectiveness of the class of antiepileptic drugs which target GABA metabolism , e.g., vigabitrin, gabapentin, tiagabine, depend on the elevation of GABA concentration. The focus of this proposal is the regulation of GABA and homocarnasine concentrations in patients with epilepsy. Three aims propose to examine prospectively changes in occipital lobe GABA and homocarnazine induced by vigabatrin, gabapentin, and tiagabine. The purpose is to improve AED selection by developing guidelines based on GABA and homocarnosine levels. These NMRS measurements may provide a rational approach in selecting an appropriate drug. This proposal is the first attempt to provide estimates of "therapeutic levels" for brain GABA and homocarnosine, similar to serum AED levels in widespread clinical use. The fourth aim proposes to examine prospectively whether temporal lobectomy alters occipital lobe GABA and homocarnosine concentrations. The answer may impact both patient selection and the long-term post-surgical management. In the past decade, magnetic resonance methods have become standard of care in the evaluation of human epilepsy. NMRS based measurements of neurotransmitters and modulators should enter the clinical armamentarium in the next decade. This proposal will advance clinical care of seizure disorders.