Electrical stimulation as a conditioning strategy for promoting and accelerating peripheral nerve regeneration

Exp Neurol. 2018 Apr;302:75-84. doi: 10.1016/j.expneurol.2017.12.013. Epub 2017 Dec 29.


The delivery of a nerve insult (a "conditioning lesion") prior to a subsequent test lesion increases the number of regenerating axons and accelerates the speed of regeneration from the test site. A major barrier to clinical translation is the lack of an ethically acceptable and clinically feasible method of conditioning that does not further damage the nerve. Conditioning electrical stimulation (CES), a non-injurious intervention, has previously been shown to improve neurite outgrowth in vitro. In this study, we examined whether CES upregulates regeneration-associated gene (RAG) expression and promotes nerve regeneration in vivo, similar to a traditional nerve crush conditioning lesion (CCL). Adult rats were divided into four cohorts based on conditioning treatment to the common peroneal (fibular) nerve: i) CES (1h, 20Hz); ii) CCL (10s crush); iii) sham CES (1h, 0Hz); or iv) naïve (unconditioned). Immunofluorescence and qRT-PCR revealed significant RAG upregulation in the dorsal root ganglia of both CES and CCL animals, evident at 3-14days post-conditioning. To mimic a clinical microsurgical nerve repair, all cohorts underwent a common peroneal nerve cut and coaptation one week following conditioning. Both CES and CCL animals increased the length of nerve regeneration (3.8-fold) as well as the total number of regenerating axons (2.2-fold), compared to the sham and naïve-conditioned animals (p<0.001). These data support CES as a non-injurious conditioning paradigm that is comparable to a traditional CCL and is therefore a novel means to potentially enhance peripheral nerve repair in the clinical setting.

Keywords: Axon regeneration; Brain derived neurotrophic factor; Conditioning lesion; Electrical stimulation; Glial fibrillary acidic protein; Growth associated protein-43; Microsurgical repair; Nerve regeneration; Peripheral nerve; Regeneration-associated genes.

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Disease Models, Animal
  • Electric Stimulation Therapy / methods*
  • GAP-43 Protein / genetics
  • GAP-43 Protein / metabolism
  • Ganglia, Spinal / metabolism
  • Gene Expression Regulation / physiology*
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Nerve Regeneration / physiology*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Peroneal Neuropathies / pathology
  • Peroneal Neuropathies / therapy*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Brain-Derived Neurotrophic Factor
  • GAP-43 Protein
  • Glial Fibrillary Acidic Protein
  • RNA, Messenger