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）：补充应用1RO1 NS048589：“癫痫中谷氨酸对照的13C和15N MRS研究”。此补充申请被提交以完成我们4.7 Tesla MR Spectrometer升级到Bruker Avance控制台。在我们授予的赠款的特定目标中，已经取得了很大的进步，即对谷氨酰胺（GLN）从神经胶质转运到细胞外液（ECF）的传输的研究以及GLNECF神经元摄取的机制，GLNECF的机制在谷氨酸/谷氨酸/谷氨酸周期中一直缺失。为了进一步的进展，迫切需要对我们20岁的动物扫描仪进行升级。我们的特定目的＃2提议检查谷氨酸（GLU）兴奋性毒性如何引起癫痫发作。这将使用慢性海藻酸盐诱导的（KA）癫痫大鼠模型进行研究，该模型与人类颞叶癫痫（TIE）最类似。神经递质谷氨酸（GLU）过度释放到ECF和/或GLUECF对星形胶质细胞的摄取受损会导致过度刺激GLU受体和神经元变性（GLU兴奋性毒性）。 GLU释放和摄取的体内通量速率将在病变和对侧海马中测量，并与（a）电生理和行为癫痫发作相关，以及（b）直到最近在验尸中检测到的组织学变化。 MRI/太太的最新进展提出了令人兴奋的可能性，即组织或代谢变化，例如苔藓纤维发芽（在人类TLE和KA大鼠中观察到），神经元变性，神经元标记N-乙酰基天haspartate的降低，以及由于星形镜肿胀而导致的非融合物，从1-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2--升级到Bruker Avance控制台将提供最先进的成像和光谱能力，该功能可以允许对KA大鼠这些变化的非侵入性纵向监测。这将允许（a）癫痫发作和传播与海马子区域的形态和代谢变化相关，以及（b）癫痫发作是GLU释放异常的结果，GLIAL转运蛋白的GLU清除率受损，或者是这些过程的组合。这些研究将共同​​有助于更好地理解KA模型中GLN/GLU循环的调节事件，并导致对人癫痫中兴奋性毒性的更有效预防。