Glutamate/glutamine cycling in epileptic focus

脑内谷氨酸浓度的调节对癫痫控制具有重要意义。神经胶质和神经元的摄取终止这种兴奋性神经递质的作用。在神经胶质中，谷氨酸被转化为谷氨酰胺，谷氨酰胺被返回神经元用于谷氨酸的再合成。在致癫痫的人海马中，发作后谷氨酸清除延长了近三倍。这些发现表明谷氨酸清除机制，即，谷氨酸-谷氨酰胺循环，在癫痫病灶中效果较差。对复杂部分性癫痫发作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发作病灶相关，包括能量电荷减少。正电子发射断层扫描显示弥漫性发作间隙代谢低下，最大降幅通常集中在致癫痫区域。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。使用在体内和体外NMRS测量13 C标记流从谷氨酸到谷氨酰胺在大鼠和人类，我们表明，神经元释放和神经胶质清除谷氨酸（谷氨酸-谷氨酰胺循环）是一个高度活跃的代谢途径与通量成本的葡萄糖摄取。在大鼠皮层中，谷氨酸-谷氨酰胺循环的速率与葡萄糖氧化接近一比一的化学计量，并随着脑电活动的减少而减少。这些发现表明，神经元和神经胶质细胞的能量代谢是至关重要的正常谷氨酸释放和清除。我们建议测量医学难治性内侧颞叶癫痫患者海马和颞叶新皮质中谷氨酸-谷氨酰胺循环的速率。基于先导性数据，我们形成了以下假设：发作间期谷氨酸-谷氨酰胺循环在致痫性海马和颞叶新皮层中减少，并伴有发作间期峰化。在发作间期，谷氨酸循环减少反映神经胶质功能障碍。

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.