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

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 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.

Oncomodulin links inflammation to optic nerve regeneration

“…However, the physiological significance of Ocm has been unclear in the absence of evidence showing that it is actually expressed by inflammatory cells that infiltrate the eye after lens injury or Zymosan, or that it plays an essential role in inflammation-induced regeneration in vivo. In addition, there have been reports that factors other than Ocm can induce regeneration in this system (18)(19)(20), that depletion of macrophages or Ocm does not affect regeneration (20,21), and that Ocm is undetectable in the eye after lens injury (21). Our results contradict these latter findings.…”

“…It remains possible, however, that CNTF could contribute to the effects of intraocular inflammation in enhancing RGC survival (20,28). The combination of NGF, NT3 and FGF2 has also been reported to promote axon regeneration in the optic nerve (18), although the cellular mechanisms and physiological significance of these findings are presently unknown.…”

“…It is not known, however, whether Ocm is expressed by macrophages physiologically or contributes to inflammation-induced regeneration in vivo. Injection of other trophic factors has also been shown to stimulate regeneration in the optic nerve (18)(19)(20), and one group reported that they were unable to detect Ocm in the eye after inducing inflammation and that a partial depletion of macrophages did not attenuate regeneration following lens injury (21). To understand the mechanistic links between inflammation and CNS regeneration, we have used several approaches to investigate the expression and functional role of Ocm.…”

Stem Cell Based Therapies for Glaucoma

“…Distinct growth factors have been identified which may affect optic nerve regeneration. A combination of fibroblast growth factor 2 (FGF2), neurotrophin 3 (NT3) and brain derived neurotrophic factor (BDNF) (Logan et al, 2006) has been reported to stimulate axonal outgrowth of RGCs. Furthermore a range of molecules have been identified, which can reduce dendrite formation, e.g.…”

Tyrosine kinase A, C and fibroblast growth factor-2 receptors in bovine embryos cultured in vitro

“…NTs also bind to the low-affinity p75 neurotrophin receptor (p75 NTR ). NTs may strengthen their effects by cooperation both among them and with the basic fibroblast growth factor (bFGF) [3,4]. The bFGF belongs to the fibroblast growth factor (FGF) family, whose members are involved in angiogenesis, wound healing, and embryonic development [5].…”