Experimental strategies to promote functional recovery after peripheral nerve injuries.
The capacity of Schwann cells (SCs) in the peripheral nervous system to support axonal regeneration, in contrast to the oligodendrocytes in the central nervous system, has led to the misconception that peripheral nerve regeneration always restores function. Here, we consider how prolonged periods of time that injured neurons remain without targets during axonal regeneration (chronic axotomy) and that SCs in the distal nerve stumps remain chronically denervated (chronic denervation) progressively reduce the number of motoneurons that regenerate their axons. We demonstrate the effectiveness of low-dose, brain-derived neurotrophic and glial-derived neurotrophic factors to counteract the effects of chronic axotomy in promoting axonal regeneration. High-dose brain-derived neurotrophic factor (BDNF) on the other hand, acting through the p75 receptor, inhibits axonal regeneration and may be a factor in stopping regenerating axons from forming neuromuscular connections in skeletal muscle. The immunophilin, FK506, is also effective in promoting axonal regeneration after chronic axotomy. Chronic denervation of SCs (>1 month) severely deters axonal regeneration, although the few motor axons that do regenerate to reinnervate muscles become myelinated and form enlarged motor units in the reinnervated muscles. We found that in vitro incubation of chronically denervated SCs with transforming growth factor-beta re-established their growth-supportive phenotype in vivo, consistent with the idea that the interaction between invading macrophages and denervated SCs during Wallerian degeneration is essential to sustain axonal regeneration by promoting the growth-supportive SC phenotype. Finally, we consider the effectiveness of a brief period of 20 Hz electrical stimulation in promoting the regeneration of axons across the surgical gap after nerve repair.
Gordon
Tessa
T
Center for Neuroscience, Division of Physical Medicine and Rehabilitation, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. tessa.gordon@ualberta.ca
Sulaiman
Olawale
O
Boyd
J Gordon
JG
D000818:Animals; D017763:Autonomic Denervation / Q000379:methods; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D019771:Axotomy / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000627:therapeutic use; D002452:Cell Count; D005576:Colforsin / Q000494:pharmacology; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D019054:Evoked Potentials, Motor / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000528:radiation effects; D009119:Muscle Contraction / Q000502:physiology; D009410:Nerve Degeneration / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D009416:Nerve Regeneration / Q000187:drug effects / Q000528:radiation effects; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D020813:Receptor, trkB / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000528:radiation effects; D012235:Rhodamines / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D003911:Dextrans; C067661:Fluoro-Ruby; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012235:Rhodamines; D016212:Transforming Growth Factor beta; D005576:Colforsin; D020813:Receptor, trkB; D016559:Tacrolimus