Glutamate/glutamine cycling in epileptic focus

脑谷氨酸浓度的调节对癫痫发作的控制具有重要意义。胶质细胞和神经元的摄取终止了这种兴奋性神经递质的作用。在神经胶质细胞中，谷氨酸转化为谷氨酰胺，谷氨酰胺返回神经元进行谷氨酸的谷氨酸再合成。在致癫痫的人类海马体中，癫痫后谷氨酸清除时间延长了近三倍。这些发现表明，谷氨酸清除机制，即谷氨酸-谷氨酰胺循环，在癫痫发作的焦点不太有效。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发作焦点相关，包括能量电荷减少。正电子发射断层扫描显示弥漫性间期代谢降低，最大程度的降低通常集中在致痫区。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nmr测量大鼠和人体内谷氨酸到谷氨酰胺的13C标签流，我们发现谷氨酸的神经元释放和胶质清除（谷氨酸-谷氨酰胺循环）是一个高度活跃的代谢途径，其通量成本高于葡萄糖摄取途径。在大鼠皮层中，谷氨酸到谷氨酰胺的循环速率与葡萄糖氧化呈近一比一的化学计量，并随着脑电活动的减少而降低。这些发现表明，神经元和神经胶质的能量代谢对正常的谷氨酸释放和清除至关重要。我们拟测量难治性内侧颞叶癫痫患者海马和颞叶新皮层谷氨酸-谷氨酰胺循环速率。基于试验数据，我们形成了以下假设：在癫痫发作的海马和颞叶新皮层中，谷氨酸-谷氨酰胺循环随着间期尖峰而减少。在间期状态下，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.