Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury.
OBJECTIVE
Injured peripheral nerves regenerate at very slow rates. Therefore, proximal injury sites such as the brachial plexus still present major challenges, and the outcomes of conventional treatments remain poor. This is in part attributable to a progressive decline in the Schwann cells' ability to provide a supportive milieu for the growth cone to extend and to find the appropriate target. These challenges are compounded by the often considerable delay of regeneration across the site of nerve laceration. Recently, low-frequency electrical stimulation (as brief as an hour) has shown promise, as it significantly accelerated regeneration in animal models through speeding of axon growth across the injury site.


METHODS
To test whether this might be a useful clinical tool, we carried out a randomized controlled trial in patients who had experienced substantial axonal loss in the median nerve owing to severe compression in the carpal tunnel. To further elucidate the potential mechanisms, we applied rolipram, a cyclic adenosine monophosphate agonist, to rats after axotomy of the femoral nerve.


RESULTS
We demonstrated that effects similar to those observed in animal studies could also be attained in humans. The mechanisms of action of electrical stimulation likely operate through up-regulation of neurotrophic factors and cyclic adenosine monophosphate. Indeed, the application of rolipram significantly accelerated nerve regeneration.


CONCLUSIONS
With new mechanistic insights into the influencing factors of peripheral nerve regeneration, the novel treatments described above could form part of an armament of synergistic therapies that could make a meaningful difference to patients with peripheral nerve injuries.
Gordon
Tessa
T
Center for Neuroscience, Division of Neuroscience, Faculty of Medicine, University of Alberta, Edmonton, Canada. tessa.gordon@ualberta.ca
Chan
K Ming
KM
Sulaiman
Olawale A R
OA
Udina
Esther
E
Amirjani
Nasim
N
Brushart
Thomas M
TM
D000818:Animals; D000242:Cyclic AMP / Q000819:agonists* / Q000378:metabolism; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy / Q000379:methods*; D020439:Growth Cones / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology / Q000628:therapy*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D020889:Rolipram