Centre for Neuroscience, The University of Melbourne, Parkville, Victoria, Australia.
PLoS One. 2011;6(9):e24636. doi: 10.1371/journal.pone.0024636. Epub 2011 Sep 13.
Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.
发育轴突导向分子（如神经信号素和 Eph 受体酪氨酸激酶家族成员及其配体 Ephrins）的上调和激活，在中枢神经系统损伤后抑制轴突再生中发挥作用。我们之前在基因敲除模型中证明，在缺乏轴突导向蛋白 EphA4 的情况下，脊髓损伤后的轴突再生会得到促进。因此，EphA4 的拮抗作用被提出作为促进脊髓损伤恢复的一种潜在治疗方法。为了进一步评估这种潜力，我们研究了两种可溶性重组 EphA4 阻断剂，未聚类的 Ephrin-A5-Fc 和 EphA4-Fc，以评估它们在野生型小鼠脊髓半切后促进轴突再生和改善功能结果的能力。在脊髓损伤后 2 周内给予这两种阻断剂中的任何一种，都足以在损伤后 5 周内促进大量轴突再生和功能恢复。两种抑制剂都使星形胶质细胞增生适度减少，表明阻断剂的大部分作用可能是由于促进轴突生长。这些研究提供了明确的证据，表明 EphA4 功能的可溶性抑制剂为脊髓损伤的治疗提供了巨大的治疗潜力，并且可能具有治疗其他中枢神经系统损伤的更广泛潜力。
