Excitotoxic mechanisms of ischemic injury in myelinated white matter
Excitotoxic mechanisms of ischemic injury in myelinated white matter
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DOI：
10.1038/sj.jcbfm.9600455
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发表时间：
2007-09-01
影响因子：
6.3
通讯作者：
Ransom, Bruce R.
中科院分区：
文献类型：
--
作者：
Tekkoek, Selva Baltan;Ye, ZuCheng;Ransom, Bruce R.
白质轴突损伤和功能障碍是由包括脑缺血在内的多种神经系统疾病引起的。我们研究了单纯有髓WM束--小鼠视神经(MON)的缺血性损伤和谷氨酸介导的兴奋性毒性的作用。首次将兴奋性毒性WM损伤与谷氨酸释放直接相关。缺氧缺糖(OGD)引起幼年小鼠视神经轴突功能的持续时间依赖性丧失。保护轴突功能需要阻断alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic酸(AMPA)和红藻氨酸受体，或移除细胞外呼叫。阻断N-甲基-D-天冬氨酸受体不能保留轴突功能。奇怪的是，即使长时间直接暴露在谷氨酸、海人酸或AMPA中，也没有引起轴突功能障碍。然而，短暂的OGD会导致谷氨酸受体激动剂的暴露变得有毒，这表明离子干扰使兴奋性毒性损伤成为可能。用定量高效液相色谱直接测量的谷氨酸释放，发生在OGD的60分钟后期，是由于谷氨酸转运体的逆转。短暂的OGD(即15分钟)不会引起谷氨酸的释放，并且产生的伤害很小。这些结果表明，OGD过程中谷氨酸的毒性积累遵循最初的离子变化，介导了早期兴奋性的丧失。谷氨酸释放是不可逆脑缺血损伤的重要阈值事件。介导WM缺血损伤的特异性谷氨酸受体似乎存在地区差异。对于缺血性西医损伤的治疗必须进行相应的设计。
Axonal injury and dysfunction in white matter (WM) are caused by many neurologic diseases including ischemia. We characterized ischemic injury and the role of glutamate-mediated excitotoxicity in a purely myelinated WM tract, the mouse optic nerve (MON). For the first time, excitotoxic WM injury was directly correlated with glutamate release. Oxygen and glucose deprivation (OGD) caused duration-dependent loss of axon function in optic nerves from young adult mice. Protection of axon function required blockade of both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or removal of extracellular Call. Blockade of N-methyl-D-aspartate receptors did not preserve axon function. Curiously, even extended periods of direct exposure to glutamate or kainate or AMPA failed to induce axon dysfunction. Brief periods of OGD, however, caused glutamate receptor agonist exposure to become toxic, suggesting that ionic disruption enabled excitotoxic injury. Glutamate release, directly measured using quantitative high-performance liquid chromatography, occurred late during a 60-mins period of OGD and was due to reversal of the glutamate transporter. Brief periods of OGD (i.e., 15 mins) did not cause glutamate release and produced minimal injury. These results suggested that toxic glutamate accumulation during OGD followed the initial ionic changes mediating early loss of excitability. The onset of glutamate release was an important threshold event for irreversible ischernic injury. Regional differences appear to exist in the specific glutamate receptors that mediate WM ischemic injury. Therapy for ischernic WM injury must be designed accordingly.