Conditioning electrical stimulation fails to enhance sympathetic axon regeneration.

Peripheral nerve injuries are common, and there is a critical need for the development of novel therapeutics to complement surgical repair. Conditioning electrical stimulation (CES) is a novel variation to the well-studied perioperative electrical stimulation, both of which have displayed success in enhancing the regeneration of motor and sensory axons in an injured peripheral nerve. CES is a clinically attractive alternative not only because of its ability to be performed at the bedside prior to a scheduled nerve repair surgery, but it has also been shown to be superior to perioperative electrical stimulation in the enhancement of motor and sensory regeneration. However, the effects of CES on sympathetic regeneration are unknown. Therefore, we tested the effects of two clinically relevant CES paradigms on sympathetic axon regeneration and distal target reinnervation. Because of the long history of evidence for the enhancement of motor and sensory axons in response to electrical stimulation, we hypothesize that CES will also enhance sympathetic axon regeneration. Our results indicate that the growth of sympathetic axons is acutely inhibited by CES; however, at a longer survival time point post-injury, there is no difference between sham CES and the CES groups. There has been evidence to suggest that the growth of sympathetic axons is inhibited by a conditioning lesion, and that sympathetic axons may respond to electrical stimulation by sprouting rather than elongation. Our data indicate that sympathetic axons may retain some regenerative ability after CES, but no enhancement is exhibited, which may be accounted for by the inability of the current clinically relevant electrical stimulation paradigm to recruit the small-caliber sympathetic axons into activity. Further studies will be needed to optimize electrical stimulation parameters in order to enhance the regeneration of all neuron types.