Endocrine Abstracts

Rescuing neurons from death and promoting axon regeneration through the delivery of individual neurotrophic factors (NTF) to the CNS has proved disappointing. We evaluated in vitro the potency of FGF2, NT-3, and BDNF given singly, or in combination, to trophically support retinal ganglion cells (RGC) in the presence of inhibitory CNS myelin, and demonstrated increased survival and neurite outgrowth greater than the sum of the effects of each NTF given alone. We observed similar trophic synergism of combinatorial NTF treatment in vivo after optic nerve (ON) transection and intravitreal implantation of fibroblasts transfected with fgf2/nt-3/bdnf which promoted enhanced RGC survival and axon regeneration in the ON rich in myelin- and non-myelin-derived inhibitory ligands. Appropriately, NTF-stimulated regenerating axons completely abolish scarring in the ON. We sought to discover a mechanism for synergistic disinhibition of RGC axon growth through an analysis of the combined effects of NTF on inhibitory signalling in RGC in vitro. Triple NTF treatment activated regulated intramembranous proteolysis (RIP) of p75^NTR, leading to a reduction in intact p75^NTR and the appearance of 55 kDa extracellular domain (ECD) and 25 kDa intracellular domain (ICD) fragments (p75_ECD and p75_ICD), cleaved by the enzymes TACE and γ-secretase, respectively, and correlated with a 30% decrease in levels of activated Rho-A, a key downstream signalling molecule in the axon growth inhibitory cascade. We conclude that perisomatic delivery of combinations of NTF synergistically promotes CNS neuronal survival and disinhibits axon growth, leading to a failure in scarring.