Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury.
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.
Logan
Ann
A
Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK. a.logan@bham.ac.uk
Ahmed
Zubair
Z
Baird
Andrew
A
Gonzalez
Ana Maria
AM
Berry
Martin
M
D000818:Animals; D001369:Axons / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000627:therapeutic use; D002478:Cells, Cultured; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000627:therapeutic use; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D007150:Immunohistochemistry; D007267:Injections; D009186:Myelin Sheath; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D009416:Nerve Regeneration; D009474:Neurons / Q000648:ultrastructure; D020933:Neurotrophin 3 / Q000235:genetics / Q000627:therapeutic use; D009900:Optic Nerve / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D012165:Retinal Ganglion Cells / Q000187:drug effects; D014161:Transduction, Genetic; D014822:Vitreous Body
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; C019277:brain-derived growth factor; D016222:Fibroblast Growth Factor 2