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：“谷氨酸控制癫痫的 13C 和 15N MRS 研究”。提交此补充申请是为了完成我们的 4.7 Tesla MR 光谱仪到 Bruker Avance 控制台的升级。我们授予的资助的具体目标 #1 已取得实质性进展，即研究谷氨酰胺 (GLN) 从神经胶质细胞转运到细胞外液 (ECF) 的动力学以及神经元摄取 GLNECF 的机制，这一直是缺失的谷氨酰胺/谷氨酸循环中的环节。为了取得进一步的进展，我们迫切需要对已有 20 年历史的动物扫描仪进行升级。我们的具体目标#2 建议研究谷氨酸 (GLU) 兴奋性毒性如何导致癫痫发作。这将使用慢性红藻氨酸诱导（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。 ECF 中神经递质谷氨酸 (GLU) 的过度释放和/或星形胶质细胞对 GLUECF 的摄取受损可能导致 GLU 受体过度刺激和神经元变性（GLU 兴奋性毒性）。将在受损海马和对侧海马中测量 GLU 释放和摄取的体内通量率，并将其与 (a) 电生理和行为癫痫发作以及 (b) 形态变化相关联，直到最近，这些变化才在死后大脑中通过组织学检测到。 MRI/MRS 的最新进展提出了一种令人兴奋的可能性，即组织病理学或代谢变化，例如苔藓纤维出芽（在人类 TLE 和 KA 大鼠中观察到）、神经元变性、神经元标记物 N-乙酰天冬氨酸减少以及星形胶质细胞肿胀引起的水肿，可以从 1-2 微升啮齿动物大脑中进行非侵入性检测。升级到 Bruker Avance 控制台将提供最先进的成像和光谱功能，可以对 KA 大鼠的这些变化进行非侵入性纵向监测。这将有助于确定 (a) 癫痫发作和传播如何与海马亚区域的形态和代谢变化相关，以及 (b) 癫痫发作是否是 GLU 释放异常、神经胶质转运蛋白 GLU 清除受损的结果，或这些过程的组合。这些研究将有助于更好地理解 KA 模型中 GLN/GLU 循环的调节事件，并更有效地预防人类癫痫的兴奋性毒性。