Brain Advance Access originally published online on December 9, 2005
Brain 2006 129(2):490-502; doi:10.1093/brain/awh706
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Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury
Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK
*Correspondence to: Professor Ann Logan, Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK E-mail: a.logan{at}bham.ac.uk
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 p75NTR, 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.
Key Words: Neurotrophic factors; regulated intramembrane proteolysis; optic nerve regeneration; p75NTR; CNS
Abbreviations: BDNF = brain derived neurotrophic factor; FGF2 = fibroblast growth factor; NT-3 = neurotrophin-3; NgR = Nogo receptor
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Received July 5, 2005. Revised September 21, 2005. Accepted October 27, 2005.
* These authors contributed equally to this work.
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