ENERGY AND METABOLISM IN TEMPORAL LOBE EPILEPSY

包括FDGPET和MRS在内的各种代谢成像研究表明，某些症状性癫痫的致痫区域存在代谢和能量缺陷。特别是，N-乙酰天冬氨酸(NAA)的1H核磁共振测量可能表明线粒体功能障碍，而31P核磁共振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。为了控制难治性癫痫发作，从这些患者身上取出的海马区组织显示细胞色素C氧化酶(COX)和Na/k-ATPase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丢失。在活体海马区的微透析研究表明，谷氨酸转运体功能障碍是一个重要的功能环节，低能量状态与谷氨酸清除不良和过度兴奋有关。因此，这项研究假设MTLE可能存在能量折衷，引发兴奋性级联反应，谷氨酸代谢不足，神经元-神经胶质神经递质循环改变，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31P核磁共振检查高能磷酸盐(PCR和ATP)，以及用NAA的1H核磁共振检查神经元功能障碍来解决这一假设。这些三羧酸(TCA)13C的测量以及谷氨酸循环和谷氨酰胺合成的阻滞率将在体内与对照组进行处理，并与项目2中描述的切除组织的体外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、增殖和DNA分析以及COX和谷氨酸转运蛋白相关联。最后，这一假说的功能后果将在项目4中进行测试，检查人类和对照红藻氨酸大鼠模型中ECF空间、K+和谷氨酸的调节。

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.