Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats
Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats
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DOI：
10.1093/brain/awn133
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发表时间：
2008-08-01
期刊：
影响因子：
14.5
通讯作者：
de Lanerolle, Nihal C.
中科院分区：
文献类型：
--
作者：
Eid, Tore;Ghosh, Arko;de Lanerolle, Nihal C.
海马细胞外谷氨酸过量与难治性内侧颞叶癫痫 (MTLE) 患者反复发作和脑部病理有关。然而，导致 MTLE 谷氨酸过量的机制仍不清楚。我们最近报道，MTLE 患者海马中谷氨酸代谢酶谷氨酰胺合成酶缺乏，我们推测这种缺乏与该疾病的病理生理学密切相关。为了进一步探讨谷氨酰胺合成酶在 MTLE 中的作用，我们通过单侧连续（大约 28 天）微量输注蛋氨酸亚磺酰亚胺（MSO：0.625 至 2.5 μg/h）建立了海马谷氨酰胺合成酶缺乏症的新型动物模型。与盐水相比，这种治疗导致海马谷氨酰胺合成酶活性降低 82-97%。大多数 (>95%) 接受 MSO 治疗的动物表现出持续数周的反复癫痫发作。一些接受 MSO 治疗的动物表现出与内侧颞叶硬化相似的神经病理学特征，例如海马萎缩和海马神经元的模式性丢失。然而，许多接受 MSO 治疗的动物仅表现出轻微的海马损伤，没有明显的颞叶内侧硬化证据。这些发现支持这样的假设：即使没有典型的内侧颞叶硬化，海马谷氨酰胺合成酶的缺乏也会导致复发性癫痫发作，并且谷氨酰胺合成酶的恢复可能代表了治疗干预该疾病的一种新方法。
An excess of extracellular glutamate in the hippocampus has been linked to the generation of recurrent seizures and brain pathology in patients with medically intractable mesial temporal lobe epilepsy (MTLE). However, the mechanism which results in glutamate excess in MTLE remains unknown. We recently reported that the glutamate-metabolizing enzyme glutamine synthetase is deficient in the hippocampus in patients with MTLE, and we postulated that this deficiency is critically involved in the pathophysiology of the disease. To further explore the role of glutamine synthetase in MTLE we created a novel animal model of hippocampal glutamine synthetase deficiency by continuous (similar to 28 days) microinfusion of methionine sulfoximine (MSO: 0.625 to 2.5 mu g/h) unilaterally into the hippocampus in rats. This treatment led to a deficiency in hippocampal glutamine synthetase activity by 82-97% versus saline. The majority (>95%) of the MSO-treated animals exhibited recurrent seizures that continued for several weeks. Some of the MSO-treated animals exhibited neuropathological features that were similar to mesial temporal sclerosis, such as hippocampal atrophy and patterned loss of hippocampal neurons. However, many MSO-treated animals displayed only minimal injury to the hippocampus, with no clear evidence of mesial temporal sclerosis. These findings support the hypothesis that a deficiency in hippocampal glutamine synthetase causes recurrent seizures, even in the absence of classical mesial temporal sclerosis, and that restoration of glutamine synthetase may represent a novel approach to therapeutic intervention in this disease.