Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?
Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?
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DOI：
10.3389/fnins.2015.00469
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发表时间：
2015
影响因子：
4.3
通讯作者：
Maher P
中科院分区：
文献类型：
--
作者：
Lewerenz J;Maher P
与天冬氨酸一起，谷氨酸是大脑中主要的兴奋性神经递质。谷氨酸结合并激活配体门控离子通道（离子型谷氨酸受体）和一类G蛋白偶联受体（代谢型谷氨酸受体）。虽然脑中的细胞内谷氨酸浓度在毫摩尔范围内，但通过将谷氨酸和天冬氨酸输入星形胶质细胞和神经元的兴奋性氨基酸转运蛋白的作用，细胞外谷氨酸浓度保持在低微摩尔范围内。过量的细胞外谷氨酸可通过离子型谷氨酸受体的过度激活在体外和体内引起急性损伤如缺血性卒中的兴奋性毒性。此外，慢性兴奋性毒性已被假设在许多神经退行性疾病中起作用，包括肌萎缩性侧索硬化症、阿尔茨海默病和亨廷顿病。基于这一假设，大量的努力已经致力于开发和测试药物，无论是抑制谷氨酸受体或减少细胞外谷氨酸。在这篇综述中，我们提供了一个概述的不同途径，被认为是导致过度激活的谷氨酸能系统和谷氨酸毒性的神经退行性疾病。此外，我们总结了现有的实验证据谷氨酸毒性的神经退行性疾病的动物模型。
Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.