Glutamate/glutamine cycling in epileptic focus

脑内谷氨酸浓度的调节对控制癫痫发作具有重要意义。神经胶质和神经元的摄取终止了这种兴奋性神经递质的作用。在胶质细胞中，谷氨酸被转化为谷氨酰胺，谷氨酰胺返回神经元，用于谷氨酸的重新合成。癫痫发作后人类海马区谷氨酸清除时间延长近三倍。这些发现表明，谷氨酸清除机制，即谷氨酸-谷氨酰胺循环，在癫痫灶中效果较差。对复杂部分性癫痫患者的体内磁共振波谱(NMRS)研究表明，线粒体代谢缺陷与癫痫灶有关，包括能量电荷减少。正电子发射断层扫描显示发作期弥漫性低代谢，最大值减少通常集中在致痫区域。葡萄糖氧化是成熟大脑中用于支持神经元活动的主要能量来源。利用体内和体外NMRS测量大鼠和人从谷氨酸到谷氨酰胺的~(13)C标记流，我们发现神经元对谷氨酸的释放和胶质清除(谷氨酸-谷氨酰胺循环)是一条高度活跃的代谢途径，其流量成本高于葡萄糖摄取。在大鼠大脑皮层，谷氨酸与谷氨酰胺循环的比率与葡萄糖氧化的化学计量比接近一比一，并随着脑电活动的减少而降低。这些发现表明，神经元和神经胶质细胞的能量代谢对于正常的谷氨酸释放和清除都是至关重要的。我们建议测量药物难治性内侧颞叶癫痫患者海马区和颞叶新皮质谷氨酸-谷氨酰胺循环率。基于实验数据，我们形成了以下假设：癫痫发作间歇期谷氨酸-谷氨酰胺循环在致痫的海马区和伴有发作间期峰的颞叶新皮质中减少。在发作间歇期，谷氨酸循环减少反映了神经胶质细胞功能障碍。

The regulation of brain glutamate concentration is of great importance for seizure control. Glial and neuronal uptake terminate the action of this excitatory neurotransmitter. In glia, glutamate is converted to glutamine which is returned to neurons for the resynthesis of glutamate of glutamate. Post-ictal glutamate clearance is prolonged nearly three fold in the epileptogenic human hippocampus. These findings suggest that glutamate clearance mechanisms, i.e., the glutamate-glutamine cycle, are less effective in the seizure focus. In vivo magnetic resonance spectroscopy (NMRS) studies of patients with complex partial seizures suggest mitochondrial metabolic deficiencies are associated with the seizure focus including decreased energy charge. Positron emission tomography reveals diffuse interictal hypometabolism with the maximum decreased usually centered in the epileptogenic region. Glucose oxidation is the major energy source in the mature brain used to support neuronal activity. Using in vivo and in vitro NMRS to measure the 13C label flows from glutamate to glutamine in rats and humans, we showed that the neuronal release and glial clearance of glutamate (glutamate-glutamine cycle) is a highly active metabolic pathway with a flux cost to that of glucose uptake. In rat cortex, the rate of the glutamate to glutamine cycle is in a near one to one stoichiometry with glucose oxidation and decreases with decreasing brain electrical activity. These findings suggest that both neuronal and glial energy metabolism are critical for normal glutamate release and clearance. We proposed to measure the rate of glutamate - glutamine cycling in the hippocampus and temporal neocortex of patients with medically refractory mesial temporal lobe epilepsy. Based on pilot data, we formed the following hypotheses: interictal glutamate-glutamine cycling is decreased in the epileptogenic hippocampus and temporal neocortex with interictal spiking. In the interictal state, decreased glutamate cycling reflects glial dysfunction.