Glutamine Synthetase and the Mechanism of Seizures in Mesial Temporal Lobe Epilep

谷氨酰胺合成酶和内侧颞叶癫痫发作的机制

• 批准号: 8899981
• 负责人: TORE EID
• 金额: $ 3.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899981
• 关键词: Address; Ammonia; Antiepileptic Agents; Astrocytes; Biological Markers; Brain; Brain Injuries; Brain Pathology; Chemicals; Chronic; Diagnosis; Diagnostic tests; Disease; Drug resistance; Electroencephalography; Electron Microscopy; Enzymes; Epilepsy; Event; Excitatory Amino Acids; Extracellular Space; Focal Seizure; Generations; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Goals; Health; Hippocampus (Brain); Histology; Hour; Human; Individual; Isotope Labeling; Laboratories; Mass Spectrum Analysis; Methods; Microdialysis; Modeling; Monitor; Pathology; Patients; Potassium; Rattus; Recurrence; Role; Sclerosis; Seizures; Severities; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; enzyme activity; extracellular; in vivo; novel; novel diagnostics; novel strategies; restoration; tandem mass spectrometry

DESCRIPTION (provided by applicant): One of the most common types of epilepsy - mesial temporal lobe epilepsy (MTLE) - is characterized by spontaneous and recurrent partial seizures. Furthermore, many patients with MTLE cannot control their seizures with current antiepileptic drugs. Novel approaches aimed at predicting and treating impending mesial temporal lobe seizures are therefore particularly important. Thus, the overall goal of the present proposal is to explore the mechanism of seizure generation in MTLE, thereby facilitating the discovery of candidate biomarkers of and more efficacious therapies for this disorder. Recent studies have suggested that a deficiency in glutamine synthetase in the hippocampus is implicated in the generation of seizures in MTLE (Eid et al. Lancet 2004; 363: 28-37). Using state-of-the art methods in continuous video intracranial EEG monitoring, microdialysis, immunogold electron microscopy, 13C- and 15N-isotope labeling, and tandem mass spectrometry, the role of the glutamine synthetase deficiency in the generation of seizures will be systematically explored in a newly developed laboratory model of MTLE. In Specific Aim 1, the relationship among hippocampal glutamine synthetase deficiency, intra- and extracellular glutamate concentrations, seizures, and hippocampal pathology will be assessed. The hypothesis is that a deficiency in glutamine synthetase leads to chronic high concentrations of glutamate in astrocytes and the extracellular space of the hippocampus with particularly high glutamate levels in individuals suffering from severe seizures and extensive brain damage. In Specific Aim 2, transient elevations in naturally occurring brain chemicals will be explored as potential triggers of "spontaneous" seizures in MTLE. The hypothesis is that such triggers cause a transient surge in extracellular glutamate in the hippocampus with "spontaneous" seizures as the ultimate consequence. Finally, in Specific Aim 3, the concept that restoration of glutamine synthetase in the epileptogenic hippocampus may be used as a cure of MTLE will be evaluated. The hypothesis is that restoration of glutamine synthetase in the hippocampus leads to cessation of seizures even in the presence of extensive brain pathology.

描述（由申请人提供）：最常见的癫痫 - 中颞叶癫痫（MTLE）的类型之一 - 以自发和经常性的部分癫痫发作为特征。此外，许多MTLE患者无法用当前的抗癫痫药控制癫痫发作。因此，旨在预测和治疗即将到来的近颞叶癫痫发作的新方法特别重要。因此，本提案的总体目标是探索MTLE癫痫发作的机制，从而促进对这种疾病的候选生物标志物的发现和更有效的疗法。 最近的研究表明，海马中谷氨酰胺合成酶的缺乏涉及MTLE中癫痫发作的产​​生（Eid等人Lancet 2004; 363：28-37）。在连续视频颅内脑电图监测，微透析，免疫元电子显微镜，13C和15N同位素标记以及串联质谱中，使用最先进的方法，谷氨酰胺合成酶缺陷在发作中的产生中的作用将在新开发的实验性模型中进行系统地探索。在特定的目标1中，将评估海马谷氨酰胺合成酶缺乏，细胞内和细胞外谷氨酸浓度，癫痫发作和海马病理学之间的关系。假设是，谷氨酰胺合成酶的缺乏会导致星形胶质细胞中的慢性高浓度谷氨酸和海马的细胞外空间，在患有严重癫痫发作和广泛脑损伤的个体中，谷氨酸含量特别高。在特定的目标2中，自然发生的脑化学物质中的瞬时升高将被探索为MTLE中“自发”癫痫发作的潜在触发因素。假设是，这种触发因素引起海马外细胞外谷氨酸的短暂涌动，并以“自发”癫痫发作是最终结果。最后，在特定的目标3中，可以评估癫痫发作性海马中谷氨酰胺合成酶的恢复的概念。假设是，即使在存在广泛的脑病理学的情况下，海马中谷氨酰胺合成酶的恢复也会导致癫痫发作。