Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS
Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS
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DOI：
10.1016/j.jns.2009.11.013
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发表时间：
2010-03-15
影响因子：
4.4
通讯作者：
Brusilow, William S. A.
中科院分区：
文献类型：
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作者：
Ghoddoussi, Farhad;Galloway, Matthew P.;Brusilow, William S. A.
为了改变参与兴奋性毒性的神经化学物质的水平，我们用谷氨酰胺合成酶抑制剂甲硫氨酸亚砜亚胺（MSO）治疗小鼠。由于谷氨酸毒性已被提出作为各种神经退行性疾病中运动神经元变性的机制，我们测试了MSO对过表达突变型人SOD 1（G93 A）基因的转基因小鼠的影响，该转基因小鼠是人类神经退行性疾病肌萎缩性侧索硬化症（ALS）的主要遗传形式的动物模型。这种治疗在体内降低谷氨酰胺合成酶活性在体外测量的85%。质子磁共振波谱，与魔角旋转的完整样本的脑组织，表明MSO治疗降低了60%的谷氨酰胺和谷氨酸的大脑水平的30%，在运动皮层和前纹状体，同时也影响GABA和谷胱甘肽的水平。Kaplan-Meyer生存分析显示，MSO治疗显著延长了这些小鼠的寿命8%（p
In an effort to alter the levels of neurochemicals involved in excitotoxicity, we treated mice with methionine sulfoximine (MSO), an inhibitor of glutamine synthetase. Since glutamate toxicity has been proposed as a mechanism for the degeneration of motor neurons in a variety of neurodegenerative diseases, we tested the effects of MSO on the transgenic mouse that overexpresses the mutant human SOD1(G93A) gene, an animal model for the primary inherited form of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). This treatment in vivo reduced glutamine synthetase activity measured in vitro by 85%. Proton magnetic resonance spectroscopy, with magic angle spinning of intact samples of brain tissue, showed that MSO treatment reduced brain levels of glutamine by 60% and of glutamate by 30% in both the motor cortex and the anterior striatum, while also affecting levels of GABA and glutathione. Kaplan-Meyer survival analysis revealed that MSO treatment significantly extended the lifespan of these mice by 8% (p