13C and 15N MRS study of glutamate control in epilepsy

谷氨酸控制癫痫的 13C 和 15N MRS 研究

• 批准号: 7257997
• 负责人: BRIAN David ROSS
• 金额: $ 7.5万
• 依托单位: HUNTINGTON MEDICAL RESEARCH INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257997
• 关键词: 20 year old; Animals; Arts; Astrocytes; Attenuated; Award; Behavioral; Brain; Chronic; Contralateral; Diffusion Magnetic Resonance Imaging; Edema; Epilepsy; Event; Extracellular Fluid; Glutamate Receptor; Glutamates; Glutamine; Grant; Hippocampus (Brain); Histologic; Human; Image; Invasive; Kinetics; Lead; Lesion; Link; Liquid substance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Methods; Modeling; Modification; Monitor; N-acetylaspartate; Nerve Degeneration; Neuroglia; Neurons; Process; Rate; Rattus; Recovery; Rodent; Sclerosis; Seizures; Spectrum Analysis; Swelling; Temporal Lobe Epilepsy; Tissues; excitotoxicity; human MPP1 protein; in vivo; kainate; mossy fiber; neurotransmitter release; spectroscopic imaging; uptake

DESCRIPTION (provided by applicant): Supplemental Application 1RO1 NS048589: "13C and 15N MRS study of glutamate control in epilepsy". This supplemental application is submitted to complete the upgrade of our 4.7 Tesla MR spectrometer to Bruker Avance console. Substantial progress has been made in Specific Aim #1 of our awarded Grant, viz study of the kinetics of glutamine (GLN) transport from the glia to the extracellular fluid (ECF) and the mechanism of neuronal uptake of GLNECF, which had been a missing link in the glutamine/glutamate cycle. For further progress, upgrade of our 20-year-old animal scanner is urgently needed. Our Specific Aim #2 proposes to examine how glutamate (GLU) excitotoxicity may cause epileptic seizures. This will be studied using the chronic kainate-induced (KA) epileptic rat model, which most closely resembles human temporal lobe epilepsy (TIE). Excessive release of the neurotransmitter glutamate (GLU) into ECF and/or impaired uptake of GLUECF into astrocytes can lead to excessive stimulation of the GLU receptors and to neuronal degeneration (GLU excitotoxicity). In vivo flux rates of GLU release and uptake will be measured in the lesioned and contralateral hippocampus, and correlated with (a) electrophysiological and behavioral seizures, and (b) morphological changes which had, until recently, been detected histologically in post- mortem brain. Recent advances in MRI/MRS raise an exciting possibility that histopathological or metabolic changes such as mossy fiber sprouting (observed in both human TLE and KA rats), neuronal degeneration, reduction in the neuronal marker N-acetylaspartate, and edema due to astrocyte swelling, may be detected non-invasively from 1-2 microliter of rodent brain. Upgrade to Bruker Avance console will provide state-of- the-art imaging and spectroscopy capability which can permit non-invasive longitudinal monitoring of these changes in KA rats. This will allow determination of (a) how the onset and propagation of seizures are correlated with the morphological and metabolic changes in hippocampal sub-regions, and (b) whether the seizures are the result of abnormal GLU release, impaired GLU clearance by glial transporters, or a combination of these processes. Together these studies will contribute to a better understanding of the regulatory events of the GLN/GLU cycle in the KA model and lead to more effective preventions of excitotoxicity in human epilepsy.

描述（由申请人提供）：补充申请1RO1 NS048589：“癫痫患者谷氨酸控制的13C和15N MRS研究”。提交此补充申请是为了完成我们4.7 Tesla MR光谱仪到Bruker Avance控制台的升级。我们授予的专项目标1已经取得了实质性进展，即研究谷氨酰胺（GLN）从胶质细胞转运到细胞外液（ECF）的动力学和GLNECF的神经元摄取机制，这是谷氨酰胺/谷氨酸循环中缺失的一个环节。为了进一步的进展，我们急需升级我们已有20年历史的动物扫描仪。我们的具体目标#2建议研究谷氨酸（GLU）兴奋性毒性如何引起癫痫发作。这将使用慢性盐酸盐诱导（KA）癫痫大鼠模型进行研究，该模型与人类颞叶癫痫（TIE）最相似。神经递质谷氨酸（GLU）过度释放到ECF和/或星形胶质细胞对GLU摄取受损可导致GLU受体的过度刺激和神经元变性（GLU兴奋性毒性）。GLU释放和摄取的体内通量率将在受损和对侧海马中测量，并与(a)电生理和行为癫痫发作以及(b)形态学变化相关，直到最近才在死后的大脑中检测到形态学变化。MRI/MRS的最新进展提出了一种令人兴奋的可能性，即从1-2微升的啮齿动物大脑中可以无创地检测到组织病理学或代谢变化，如苔藓纤维萌发（在人类TLE和KA大鼠中观察到）、神经元变性、神经元标记物n-乙酰天氨酸减少和星形胶质细胞肿胀引起的水肿。升级到Bruker Avance控制台将提供最先进的成像和光谱能力，可以对KA大鼠的这些变化进行非侵入性纵向监测。这将允许确定(a)癫痫发作的发生和传播如何与海马亚区形态和代谢变化相关，以及(b)癫痫发作是否是GLU释放异常、胶质转运体清除GLU受损或这些过程的组合的结果。这些研究将有助于更好地理解KA模型中GLN/GLU周期的调控事件，并导致更有效地预防人类癫痫的兴奋性毒性。