ENERGY AND METABOLISM IN TEMPORAL LOBE EPILEPSY

颞叶癫痫的能量和代谢

• 批准号: 6540153
• 负责人: DENNIS D SPENCER
• 金额: $ 117.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-13 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540153
• 关键词: bioenergetics; brain metabolism; glutamates; partial seizure; temporal lobe /cortex disorder

A variety of metabolic imaging studies, including FDG PET and MRS, have suggested metabolic and energy deficiencies in epileptogenic regions of certain symptomatic epilepsies. In particular, the 1H NMR measurements of N-acetyl aspartate (NAA) may indicate mitochondrial dysfunction and the 31P NMR demonstrates depleted high energy phosphates. The medial temporal lobe epilepsy (MTLE) patients have been the most frequently studied and localized by these methods. Hippocampal tissue removed from these patients to control medically intractable seizures has revealed cytochrome c oxidase (COX) and Na/k ATPase dysregulation also suggesting that the metabolic imaging studies may be detecting mitochondrial dysfunction or loss. In vivo hippocampal microdialysis studies have implicated glutamate transporter malfunction as a significant function link tying a low energy state to poor glutamate clearance and excess excitation. Thus, the hypothesis of this grant states that energy compromise may exist in MTLE triggering an excitatory cascade with inadequate glutamate metabolism and altered neuronal-glial neurotransmitter cycling and subsequent poor extracellular glutamate clearance leading to the spread of excitability. Project 1 will initially address this hypothesis by examining CMR glucose with FDG PET, high energy phosphates (PCr and ATP) with 31 PNMR and a neuronal dysfunction with 1H NMR of NAA. These measurements of tricarboxylic acid (TCA) 13C and anaplerotic rates of glutamate cycling and glutamine synthesis will be addressed in vivo with controls and correlated with in vitro 13C cycling rates in the resected tissue described in Project 2. Project 3 will correlate these findings with human tissue mitochondrial dysfunction, density, hyperplasia and DNA analysis along with COX and glutamate transporters. Finally, the functional consequences of this hypothesis will be tested in Project 4 examining the ECF space, k+ and glutamate regulation in the human and control kainate rat model.

多种代谢成像研究，包括FDG PET和MRS，已经提示某些症状性癫痫的致痫区存在代谢和能量不足。特别是，n -乙酰天冬氨酸（NAA）的1H NMR测量可能表明线粒体功能障碍，31P NMR显示高能磷酸盐耗尽。这些方法对内侧颞叶癫痫（MTLE）患者的研究和定位最为频繁。从这些患者身上切除海马组织以控制医学上难治性癫痫发作，发现细胞色素c氧化酶（COX）和Na/k atp酶失调，也表明代谢成像研究可能检测线粒体功能障碍或丢失。体内海马微透析研究表明，谷氨酸转运蛋白功能障碍是一个重要的功能联系，将低能量状态与谷氨酸清除不良和过度兴奋联系起来。因此，本授权的假设表明，MTLE中可能存在能量妥协，引发谷氨酸代谢不足的兴奋级联反应，改变神经元-胶质神经递质循环，随后细胞外谷氨酸清除不良，导致兴奋性扩散。项目1将首先通过FDG PET检测CMR葡萄糖，31 PNMR检测高能磷酸盐（PCr和ATP），以及NAA 1H NMR检测神经元功能障碍来验证这一假设。这些三羧酸（TCA） 13C和谷氨酸循环及谷氨酰胺合成的复变率的测量将在体内与对照进行研究，并与项目2中描述的切除组织中的体外13C循环率相关。项目3将把这些发现与人类组织线粒体功能障碍、密度、增生和DNA分析以及COX和谷氨酸转运蛋白联系起来。最后，这一假设的功能后果将在项目4中进行检验，该项目将检测人类和对照盐酸盐大鼠模型中的ECF空间、k+和谷氨酸调节。