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Brain Advance Access published online on December 9, 2005
Brain, doi:10.1093/brain/awh706
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 5, 2005
Revised September 21, 2005
Accepted October 27, 2005

Article

Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury

Ann Logan 1 * *, Zubair Ahmed 1 *, Andrew Baird 1, Ana Maria Gonzalez 1, and Martin Berry 1

1 Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK

* To whom correspondence should be addressed.
Ann Logan, E-mail: a.logan{at}bham.ac.uk


  Abstract

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.

Keywords: Neurotrophic factors; regulated intramembrane proteolysis; optic nerve regeneration; p75NTR; CNS.
*These authors contributed equally to this work.
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