Enhanced Oligodendrocyte Survival after Spinal Cord Injury in Bax-Deficient Mice and Mice with Delayed Wallerian Degeneration
Enhanced Oligodendrocyte Survival after Spinal Cord Injury in Bax-Deficient Mice and Mice with Delayed Wallerian Degeneration
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DOI：
10.1523/jneurosci.23-25-08682.2003
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发表时间：
2003-09
期刊：
影响因子：
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通讯作者：
Hongxin Dong;Alicia Fazzaro;Chuanxi Xiang;S. Korsmeyer;M. Jacquin;J. Mcdonald
中科院分区：
文献类型：
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作者：
Hongxin Dong;Alicia Fazzaro;Chuanxi Xiang;S. Korsmeyer;M. Jacquin;J. Mcdonald
通过对野生型小鼠（C57BL/6J和Bax+/+小鼠）、切断轴突的野生型小鼠和缺乏促凋亡蛋白Bax （Bax-/-）的小鼠进行T9脊髓水平半切，评估脊髓损伤（SCI）后少突胶质细胞死亡的机制。在侧白质束中，损伤后8天，同侧白质3- 7mm吻侧和尾侧半切部位明显少突胶质细胞死亡。超微结构分析和抗活化caspase-3的表达表明，8 d时少突胶质细胞的死亡主要是凋亡。与C57BL/6J小鼠相比，wds小鼠在损伤后8天选择性地保存了少突胶质细胞，切断的轴突仍可存活，这一点通过前庭脊髓束的顺行标记得到证实。然而，在损伤后30 d，当wds动物切断的轴突已经退化时，8 d保存的少突胶质细胞丢失，数量与对照C57BL/6J小鼠相当。相比之下，Bax-/-小鼠的少突胶质细胞死亡在两个时间点都被阻止。当培养的少突胶质细胞暴露于staurosporine或环孢素A（已知刺激少突胶质细胞凋亡的药物）时，来自Bax-/-小鼠而不是Bax+/+或Bax+/-小鼠的少突胶质细胞对凋亡性死亡具有抗性。相比之下，三组对盐酸盐引起的兴奋性坏死死亡同样易感。基于这些数据，我们假设脊髓损伤后白质轴突的沃勒氏变性通过触发Bax表达来消除轴突支持并诱导少突胶质细胞凋亡。
Mechanisms of oligodendrocyte death after spinal cord injury (SCI) were evaluated by T9 cord level hemisection in wild-type mice (C57BL/6J and Bax+/+ mice), Wlds mice in which severed axons remain viable for 2 weeks, and mice deficient in the proapoptotic protein Bax (Bax-/-). In the lateral white-matter tracts, substantial oligodendrocyte death was evident in the ipsilateral white matter 3-7 mm rostral and caudal to the hemisection site 8 d after injury. Ultrastructural analysis and expression of anti-activated caspase-3 characterized the ongoing oligodendrocyte death at 8 d as primarily apoptotic. Oligodendrocytes were selectively preserved in Wlds mice compared with C57BL/6J mice at 8 d after injury, when severed axons remained viable as verified by antereograde labeling of the lateral vestibular spinal tract. However, 30 d after injury when the severed axons in Wlds animals were already degenerated, the oligodendrocytes preserved at 8 d were lost, and numbers were then equivalent to control C57BL/6J mice. In contrast, oligodendrocyte death was prevented at both time points in Bax-/- mice. When cultured oligodendrocytes were exposed to staurosporine or cyclosporin A, drugs known to stimulate apoptosis in oligodendrocytes, those from Bax-/- mice but not from Bax+/+ or Bax+/- mice were resistant to the apoptotic death. In contrast, the three groups were equally vulnerable to excitotoxic necrosis death induced by kainate. On the basis of these data, we hypothesize that the Wallerian degeneration of white matter axons that follows SCI removes axonal support and induces apoptotic death in oligodendrocytes by triggering Bax expression.