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

• Published in: Experimental neurology 2018-04, Vol.302, p.75-84
• Main Authors: Senger, J.L.B., Verge, V.M.K., Macandili, H.S.J., Olson, J.L., Chan, K.M., Webber, C.A.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Axon regeneration; Brain derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Conditioning lesion; Disease Models, Animal; Electric Stimulation Therapy - methods; Electrical stimulation; Ganglia, Spinal - metabolism; GAP-43 Protein - genetics; GAP-43 Protein - metabolism; Gene Expression Regulation - physiology; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Growth associated protein-43; Microsurgical repair; Nerve regeneration; Nerve Regeneration - physiology; Neuroglia - metabolism; Neuroglia - pathology; Neurons - metabolism; Neurons - pathology; Peripheral nerve; Peroneal Neuropathies - pathology; Peroneal Neuropathies - therapy; Rats; Rats, Sprague-Dawley; Regeneration-associated genes; RNA, Messenger - metabolism
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2017.12.013

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