The role of neurotrophic factors in nerve regeneration

This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.