Logan Ann, Ahmed Zubair, Baird Andrew, Gonzalez Ana Maria, Berry Martin
Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK.
Brain. 2006 Feb;129(Pt 2):490-502. doi: 10.1093/brain/awh706. Epub 2005 Dec 9.
The therapeutic effects of individual neurotrophic factors (NTF) have proved disappointing in clinical trials for neuronal repair and axon regeneration. Here, we demonstrate NTF synergistic neuronal responses after a combination of basic fibroblast growth factor, neurotrophin-3 and brain derived growth factor delivered to the somata of retinal ganglion cells promoted greater survival and axon growth than did the sum of the effects of each NTF alone. Triple and not single NTF treatments potentiated regulated intramembraneous proteolysis of p75(NTR), and ectodomain shedding of Nogo receptor, correlated with a 30% decrease in activation of Rho-A, a key signalling molecule in the axon growth inhibitory cascade. Thus, combinatorial NTF administration synergistically enhanced neuronal survival, disinhibited axon growth and promoted axon regeneration through the hostile CNS environment without the intervention of scar tissue at the lesion site.
在针对神经元修复和轴突再生的临床试验中，单一神经营养因子（NTF）的治疗效果令人失望。在此，我们证明，将碱性成纤维细胞生长因子、神经营养因子-3和脑源性神经营养因子联合输送至视网膜神经节细胞的胞体后，NTF协同神经元反应比单独使用每种NTF的效果总和更能促进细胞存活和轴突生长。三联而非单一NTF治疗增强了p75（NTR）的调节性膜内蛋白水解以及Nogo受体的胞外域脱落，这与轴突生长抑制级联反应中的关键信号分子Rho-A的激活减少30%相关。因此，联合给予NTF可协同增强神经元存活，解除轴突生长抑制，并促进轴突在恶劣的中枢神经系统环境中再生，而无需病变部位瘢痕组织的干预。
