Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion

Abstract

The number of neurotrophic factors found in the central nervous system is rapidly growing, but their functions in vivo are largely unknown. In the peripheral nervous system they promote the survival of developing and lesioned neurons and enhance nerve fibre growth and regeneration. Here we study the effects of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) on the largest tract system leading from the brain to the spinal cord, the corticospinal tract (CST). The developing CST grows down the spinal cord during the first postnatal days and innervates its targets after a waiting period by collateral sprouting. We find that NT-3 injected locally specifically enhances this sprouting, whereas BDNF has no effect. In adult rats, injection of NT-3 (but not BDNF) into the lesioned spinal cord increases the regenerative sprouting of the transected CST. The distance of growth of the sprouts is very restricted, but application of an antibody that neutralizes myelin-associated neurite growth inhibitory proteins results in long-distance regeneration of CST fibres.

Repair of spinal cord injuries: where are we, where are we going?

“…In addition a co-operative e ect exists between the IN-1 antibody and the neurotrophins NT-3 and BDNF. Thus, when rat spinal injuries were treated with a combination of IN-1 and NT-3 larger numbers of axons regenerated for a greater distance than with either treatment alone 29 ( Figure 1a). In addition to its actions on axon regeneration IN-1 causes sprouting of various axons.…”

“…Direct application of puri®ed neurotrophins has been successful in inducing axon regeneration in the cord by itself, 28 or larger amounts of regeneration has been achieved by combining neurotrophin treatment with either anti Nogo antibodies or embryonic grafts. 3,29 The most successful neurotrophin has been NT-3, for which there are receptors on corticospinal and on large sensory axons, and corticospinal axons regenerate in large numbers past grafts of NT-3 secreting ®broblasts. 30 Nerve growth factor also promotes regeneration, but receptors for it are prominent on small pain axons, so hyperalgesia can be caused by its presence in excess.…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…While NGF has been shown to promote intraspinal sprouting of nociceptive primary afferents, 164,165 the usefulness of NGF in SCI is severely limited by its painful side effects (discussed above). 163 Exogenous NT-3 promotes sprouting of intact CST axons developmentally 197 and following rubrospinal tract ablation in adults. 184 Like neurotrophic factors, neutralizing inhibitory myelin and ECM molecules can promote sprouting of some intact systems: blocking Nogo-A promotes sprouting of adult CST axons, 198 and digestion of glial scarassociated CSPGs promotes behavioral recovery following dorsal column injury in the absence of robust regeneration of injured axons.…”

Regeneration of lesioned corticospinal tract fibers in the adult rat spinal cord under experimental conditions

“…In adult rats with bilateral transections of the dorsal half of the spinal cord, including both corticospinal tracts, we have shown an increase in branch density rostral to the lesion 2 ± 3 weeks after transection. 12,13 Whereas the tracer available at that time (wheat germ agglutinin coupled to horseradish peroxidase, WGA-HRP) did not allow single ®ber resolution, the introduction of a highly sensitive high resolution anterograde tracer, biotin-dextran-amine (BDA) now allows the visualization of this sprouting process in great detail. 14 Spinal cords of young adult (4 ± 6 week old) rats were transected at the midthoracic (T8) level in the dorsal half bilaterally 12 and BDA was injected into the sensory motor cortex.…”