Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter
Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter
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DOI：
10.1523/jneurosci.20-03-01190.2000
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发表时间：
2000-02-01
影响因子：
5.3
通讯作者：
Stys, PK
中科院分区：
文献类型：
--
作者：
Li, SX;Stys, PK
脊髓损伤涉及谷氨酸介导的白色物质损伤的一个组成部分，但涉及的细胞靶点、受体和离子知之甚少。在离体脊髓背柱的体外模型中检查兴奋性毒性的机制。在37 ℃下暴露于1 mM谷氨酸3小时后，复合动作电位（CAP）不可逆地降低至对照的43%。AMPA（100 μ M）和红藻氨酸盐（500 μ M）具有类似的效果。拮抗剂（1 mM犬尿喹啉酸、10 μ M NBQX、30 μ M GYKI 52466）各自对谷氨酸激发具有同等的保护作用，将平均CAP振幅提高至接近80%，而在没有拮抗剂的情况下提高至接近40%。Joro蜘蛛毒素（0.75 μ M），一种选择性阻断剂的Ca 2+渗透AMPA受体，也保护到类似的程度。无Ca 2+灌注液几乎消除了谷氨酸诱导的损伤（类似于90% vs类似于40%）。MK-801（10 μ M）无影响。谷氨酸引起的损害（血影蛋白分解产物的化学分析），星形胶质细胞和少突胶质细胞与GluR 2/3和GluR 4在这些细胞中的存在一致。髓鞘也可能被谷氨酸损伤，谷氨酸可能是由在该区域检测到的GluR 4受体介导的;然而，轴突圆柱体不受谷氨酸的影响，显示血影蛋白分解水平没有增加。这些数据可能指导开发更有效的治疗急性脊髓损伤的脊髓白色物质损伤的额外兴奋性毒性成分。
Spinal cord injury involves a component of glutamate-mediated white matter damage, but the cellular targets, receptors, and ions involved are poorly understood. Mechanisms of excitotoxicity were examined in an in vitro model of isolated spinal dorsal columns. Compound action potentials (CAPs) were irreversibly reduced to 43% of control after 3 hr of 1 mM glutamate exposure at 37 degrees C. AMPA (100 mu M) and kainate (500 mu M) had similar effects. Antagonists (1 mM kynurenic acid, 10 mu M NBQX, 30 mu M GYKI52466) were each equally protective against a glutamate challenge, improving mean CAP amplitude to similar to 80% versus similar to 40% without antagonist. Joro spider toxin (0.75 mu M), a selective blocker of Ca2+-permeable AMPA receptors, was also protective to a similar degree. Ca2+-free perfusate virtually abolished glutamate-induced injury (similar to 90% vs similar to 40%). MK-801 (10 mu M) had no effect. Glutamate caused damage (assayed immunohistochemically by spectrin breakdown products) to astrocytes and oligodendrocytes consistent with the presence of GluR2/3 and GluR4 in these cells. Myelin was also damaged by glutamate likely mediated by GluR4 receptors detected in this region; however, axon cylinders were unaffected by glutamate, showing no increase in the level of spectrin breakdown. These data may guide the development of more effective treatment for acute spinal cord injury by addressing the additional excitotoxic component of spinal white matter damage.