Central axons preparing to myelinate are highly sensitive [corrected] to ischemic injury.
Central axons preparing to myelinate are highly sensitive [corrected] to ischemic injury.
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准备髓鞘的中央轴突对缺血性损伤高度敏感。
DOI：
10.1002/ana.23690
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发表时间：
2012-12
影响因子：
11.2
通讯作者：
Fern, Robert
中科院分区：
文献类型：
--
作者：
Alix, James J. P.;Zammit, Christian;Riddle, Art;Meshul, Charles K.;Back, Stephen A.;Valentino, Mario;Fern, Robert
发育中的中央白色物质在髓鞘形成之前的时期受到缺血型损伤。在成熟的这个阶段，中央轴突启动径向扩张和离子通道重新分布的程序。在这里，我们测试的假设，在径向扩张轴突显示缺血敏感性提高，当集群的Ca2+通道装饰未来节点的Ranvier网站。在一段时间的模拟缺血期间和之后，中央轴突和神经胶质细胞的功能和形态进行了检查。本研究应用电生理、超微结构定量和形态计量学方法，对体外模拟缺血和体内缺氧缺血条件下新生啮齿动物视神经和脑室周围白色物质轴突的径向扩张过程中的病理变化进行了研究。急性缺血性损伤的中央轴突进行初始径向扩张介导的Ca2+内流通过Ca2+通道表达在轴膜簇。这种形式的损伤仅在该轴突群体中起作用，该轴突群体比邻近的有髓鞘轴突、尚未开始径向扩张的较小轴突、星形胶质细胞或少突胶质细胞对损伤更敏感。一种药理学策略，旨在保护小直径和大直径的前髓鞘轴突证明100%的保护急性缺血研究下模拟缺血在体外或缺氧缺血后在体内。最近的临床数据突出了轴突病理学在发展白色物质损伤中的重要性。本文所述的早熟轴突对缺血性损伤的敏感性升高可能显著有助于选择性白色物质病理学，并将这些轴突与前少突胶质细胞一起作为损伤和治疗的潜在主要靶点。
Developing central white matter is subject to ischemic-type injury during the period that precedes myelination. At this stage in maturation, central axons initiate a programme of radial expansion and ion channel re-distribution. Here we test the hypothesis that during radial expansion axons display heightened ischemic sensitivity, when clusters of Ca2+ channels decorate future node of Ranvier sites. Functionality and morphology of central axons and glia were examined during and after a period of modeled ischemia. Pathological changes in axons undergoing radial expansion were probed using electrophysiological, quantitative ultrastructural and morphometric analysis in neonatal rodent optic nerve and peri-ventricular white matter axons studied under modeled ischemia in vitro or after hypoxia-ischemia in vivo. Acute ischemic injury of central axons undergoing initial radial expansion was mediated by Ca2+ influx through Ca2+ channels expressed in axolemma clusters. This form of injury operated only in this axon population, which was more sensitive to injury than neighboring myelinated axons, smaller axons yet to initiate radial expansion, astrocytes or oligodendroglia. A pharmacological strategy designed to protect both small and large diameter pre-myelinated axons proved 100% protective against acute ischemia studied under modeled ischemia in vitro or after hypoxia-ischemia in vivo. Recent clinical data highlight the importance of axon pathology in developing white matter injury. The elevated susceptibility of early maturing axons to ischemic injury described here may significantly contribute to selective white matter pathology and places these axons alongside pre-oligodendrocytes as a potential primary target of both injury and therapeutics.
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