NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord
NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord
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DOI：
10.1046/j.1460-9568.1999.00809.x
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发表时间：
1999-11-01
影响因子：
3.4
通讯作者：
McMahon, SB
中科院分区：
文献类型：
--
作者：
Bradbury, EJ;Khemani, S;McMahon, SB
脊髓轴突的再生能力受到严重限制。近年来，人们的注意力集中在促进下行脊髓通路的再生，但对上行轴突的再生能力知之甚少。在这里，我们评估了神经营养因子促进感觉神经元再生的能力，感觉神经元的中央轴突在背柱中上升。将成年大鼠的背柱压碎，并将脑源性神经营养因子（BDNF）、胶质细胞系源性神经营养因子（GDNF）、神经营养因子-3（NT-3）或载体溶液连续递送至损伤部位4周。用霍乱毒素β亚单位（CTB）跨神经节标记来选择性标记大的有髓鞘A β纤维。在用溶剂处理的病变大鼠中，观察到CTB标记的纤维在薄束中上升，但这些纤维在病变部位突然停止，没有发芽或生长到病变组织中的证据。薄核内未见CTB标记终末，表明该损伤成功切断了所有上行背柱轴突。BDNF处理没有促进轴突再生。在GDNF处理的大鼠中，纤维在尾部变性组织的空腔周围生长，但没有接近病变中心。与此相反，NT-3，有一个显着的效果，促进损伤的背柱轴突与丰富的纤维发芽明显在病变部位的生长，和许多纤维延伸到和超出病变震中。纤维生长的定量证实，只有在NT-3治疗的大鼠纤维生长到挤压部位和超越。任何处理后，薄束核中均无明显终末染色证据。因此，虽然NT-3促进损伤轴突的广泛生长，但这些长的上行投射回到背柱核的完全再生可能需要其他因素。鞘内递送NT-3或其他神经营养分子在临床应用中具有明显的优势，因为我们第一次表明背柱轴突再生可以在不使用移植物植入或神经损伤的情况下实现。
The regeneration capacity of spinal cord axons is severely limited. Recently, much attention has focused on promoting regeneration of descending spinal cord pathways, but little is known about the regenerative capacity of ascending axons. Here we have assessed the ability of neurotrophic factors to promote regeneration of sensory neurons whose central axons ascend in the dorsal columns. The dorsal columns of adult rats were crushed and either brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) or a vehicle solution was delivered continuously to the lesion site for 4 weeks, Transganglionic labelling with cholera toxin beta subunit (CTB) was used to selectively label large myelinated A beta fibres. In lesioned rats treated with vehicle, CTB-labelled fibres were observed ascending in the gracile fasciculus, but these stopped abruptly at the lesion site, with no evidence of sprouting or growth into lesioned tissue. No CTB-labelled terminals were observed in the gracile nucleus, indicating that the lesion successfully severed all ascending dorsal column axons. Treatment with BDNF did not promote axonal regeneration. In GDNF-treated rats fibres grew around cavities in caudal degenerated tissue but did not approach the lesion epicentre. NT-3, in contrast, had a striking effect on promoting growth of lesioned dorsal column axons with an abundance of fibre sprouting apparent at the lesion site, and many fibres extending into and beyond the lesion epicentre. Quantification of fibre growth confirmed that only in NT-3-treated rats did fibres grow into the crush site and beyond. No evidence of terminal staining in the gracile nucleus was apparent following any treatment. Thus, although NT-3 promotes extensive growth of lesioned axons, other factors may be required for complete regeneration of these long ascending projections back to the dorsal column nuclei. The intrathecal delivery of NT-3 or other neurotrophic molecules has obvious advantages in clinical applications, as we show for the first time that dorsal column axonal regeneration can be achieved without the use of graft implantation or nerve lesions.