Brain-Derived Neurotrophic Factor and Neurotrophin-4/5 Stimulate Growth of Axonal Branches from Regenerating Retinal Ganglion Cells

Abstract

To investigate the influences of growth factors on axonal regeneration in the mammalian CNS, we used intracellular tracers to quantitate the effects of brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-4/5, or NT-3 on individual retinal ganglion cell (RGC) axons in the retinas of adult rats after optic nerve transection. A single injection of BDNF or the prolonged administration of NT-4/5 by mini-pump increased axon branch median lengths by eightfold but had no effect on the number of branches formed by the RGC axons. NT-3 did not significantly influence axonal regrowth. These specific in vivo effects of BDNF and NT-4/5 on axonal regeneration from injured RGCs may be used to promote growth and expand the abnormally small terminal arbors observed when RGCs regrow into their CNS targets.

Lens Injury Stimulates Axon Regeneration in the Mature Rat Optic Nerve

“…9b,e). These latter cells have been described previously in the injured retina and represent activated microglia Sawai et al, 1996;Clarke et al, 1998;Koeberle and Ball, 1998). When nerve injury was accompanied by lens puncture, RGC survival increased approximately eightfold, i.e., 24% of the original number of RGCs remained 3 weeks after surgery (430 Ϯ 38 RGCs/mm 2 : n ϭ 7).…”

“…In the rat striatum, puncture wounds stimulate microglia that express BDNF and promote the infiltration of macrophages that express GDNF; these two growth factors are likely to contribute to the survival and outgrowth of dopaminergic neurons that occurs after puncture wounds (Batchelor et al, 1999). BDNF and GDNF also affect RGC survival after axotomy Mansour-Robaey et al, 1994;Sawai et al, 1996;Di Polo et al, 1998;Koeberle and Ball, 1998) and could play a role here. However, neutralizing anti-BDNF antibodies did not diminish the positive effects of lens injury, but augmented the length of axon growth into the distal optic nerve.…”

Lesion-Induced Regulation of Netrin Receptors and Modification of Netrin-1 Expression in the Retina of Fish and Grafted Rats

“…Third, the granular reaction product is detectable in only a few RGCs, which are a small fraction of RGCs exhibiting the GAP-43 in situ hybridization signal. Finally, the turning of intraretinal axons away from the optic nerve head (Sawai et al, 1996) also occurs in lesioned rats without PN graft in which DCC and both UNC5H receptors are downregulated and in which netrin-1 is absent from the optic nerve head. Overall, it appears that downregulation of netrin-1 and of the netrin receptors partially accounts for the inability of lesioned axons to grow across the optic nerve head.…”

“…This therapy rescues RGCs from lesioninduced death, which otherwise abolishes 90% of the RGCs by 28 days (Cohen et al, 1994;Mansour-Robey et al, 1994). Repeated injection of BDNF or NT-4/5 increases the incidence of profuse axonal sprouting around the optic disk/optic nerve head region and induces long intraretinal axon branches which often turn at the optic disk/optic nerve head and grow toward the periphery (Sawai et al, 1996). This suggests lack of a growth-encouraging signal or presence of a repelling signal at the optic disk/nerve head region.…”

Spinal cord repair: from experimental models to human application

“…When the optic nerve is damaged retinal ganglion cell axon regeneration can be increased within the retina by injecting trophic factors into the eye. 12 However, the most dramatic regeneration has been produced by placing a length of peripheral nerve into the eye, which secretes a variety of factors, and allows axons to regenerate in the optic nerve itself. 13 How can axon regeneration be induced in the CNS?…”