ENERGY AND METABOLISM IN TEMPORAL LOBE EPILEPSY

包括FDG PET和MRS在内的各种代谢成像研究表明，某些症状性癫痫的致癫痫区域存在代谢和能量缺乏。特别是，N-乙酰天冬氨酸（NAA）的1H NMR测量值可能表明线粒体功能障碍，31 P NMR显示高能磷酸盐耗尽。内侧颞叶癫痫（MTLE）患者一直是最频繁的研究和定位这些方法。从这些患者中取出的用于控制药物难治性癫痫发作的海马组织显示细胞色素c氧化酶（考克斯）和Na/k ATP酶失调，这也表明代谢成像研究可能检测到线粒体功能障碍或损失。体内海马微透析研究表明谷氨酸转运体功能障碍是一个重要的功能环节，将低能状态与谷氨酸清除率差和过度兴奋联系在一起。因此，该授权的假设指出，MTLE中可能存在能量折衷，触发兴奋性级联反应，谷氨酸代谢不足，神经元-胶质细胞神经递质循环改变，随后细胞外谷氨酸清除不良，导致兴奋性扩散。项目1最初将通过用FDG PET检查CMR葡萄糖、用31 PNMR检查高能磷酸盐（PCr和ATP）以及用NAA的1H NMR检查神经元功能障碍来解决这一假设。这些三羧酸（TCA）13 C和谷氨酸循环和谷氨酰胺合成的回补率的测量将在体内与对照组一起进行，并与项目2中所述切除组织中的体外13 C循环率相关。项目3将把这些发现与人体组织线粒体功能障碍、密度、增生和DNA分析沿着考克斯和谷氨酸转运蛋白联系起来。最后，将在项目4中测试该假设的功能后果，检查人类和对照红藻氨酸大鼠模型中的ECF空间、k+和谷氨酸调节。

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.