CHRONIC INHIBITION OF GLUTAMATE UPTAKE PRODUCES A MODEL OF SLOW NEUROTOXICITY
CHRONIC INHIBITION OF GLUTAMATE UPTAKE PRODUCES A MODEL OF SLOW NEUROTOXICITY
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DOI：
10.1073/pnas.90.14.6591
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发表时间：
1993-07-15
影响因子：
11.1
通讯作者：
KUNCL, RW
中科院分区：
文献类型：
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作者：
ROTHSTEIN, JD;JIN, L;KUNCL, RW
神经递质谷氨酸转运缺陷可能是肌萎缩侧索硬化症等疾病慢性神经毒性的重要组成部分。目前还没有可靠的慢性谷氨酸神经毒性模型。大多数先前的体外系统已经研究了直接作用的谷氨酸激动剂的快速神经毒性作用。因此，我们在培养的器官型脊髓切片中建立了缓慢毒性模型。该模型基于谷氨酸转运的选择性抑制，其持续提高培养基中谷氨酸的浓度。这导致运动神经元在几周内缓慢退化。非N-甲基-D-天冬氨酸谷氨酸受体拮抗剂和谷氨酸合成或释放抑制剂可选择性预防运动神经元毒性，但N-甲基-D-天冬氨酸受体拮抗剂不能。因此，谷氨酸转运的选择性抑制产生了临床相关的缓慢神经毒性模型，并且似乎是由非N-甲基-D-天冬氨酸受体的作用介导的。这一数据支持了肌萎缩侧索硬化症运动神经元的缓慢丧失可能部分是由于谷氨酸转运缺陷的假设。
Defects in neurotransmitter glutamate transport may be an important component of chronic neurotoxicity in diseases such as amyotrophic lateral sclerosis. There are no reliable models of slow glutamate neurotoxicity. Most previous in vitro systems have studied the rapid neurotoxic effects of direct-acting glutamate agonists. Therefore, we developed a model of slow toxicity in cultured organotypic spinal cord slices. The model was based on selective inhibition of glutamate transport, which continuously raised the concentration of glutamate in the culture medium. This resulted in the slow degeneration of motor neurons over several weeks. Motor neuron toxicity was selectively prevented by non-N-methyl-D-aspartate glutamate receptor antagonists and glutamate synthesis or release inhibitors but not by N-methyl-D-aspartate receptor antagonists. Thus, selective inhibition of glutamate transport produces a model of clinically relevant slow neurotoxicity and appears to be mediated by the action of non-N-methyl-D-aspartate receptors. This data supports the hypothesis that the slow loss of motor neurons in amyotrophic lateral sclerosis could be due, in part, to defective glutamate transport.