Conditioning electrical stimulation promotes sensory and motor nerve regeneration without inducing inflammation
Christine A Webber, PhD1, Jenna-Lynn B Senger, MD, PhD1, Leah Acton, BSc2, Ashley W Chan, (BSc)1 and K. Ming Chan, MD3, (1)University of Alberta, Edmonton, AB, Canada, (2)Univeristy of Alberta, Edmonton, AB, Canada, (3)Division of Physical Medicine & Rehabilitation, University of Alberta, Edmonton, AB, Canada
Conditioning electrical stimulation promotes sensory and motor nerve regeneration without inducing inflammation
Background: Conditioning electrical stimulation (CES) delivered prior to a nerve repair promotes functional nerve regeneration beyond that of a conditioning crush lesion (CCL). Forty years of research has established that the inflammatory response evoked by the CCL injury prior to the cut and coaptation is essential to elicit the conditioning response. It is not known how CES promotes nerve regeneration.
Hypothesis: CES promotes functional nerve regeneration in a non-injurious, and non-inflammatory manner.
Methods: Sprague Dawley rats were equally divided into three cohorts: i) CES, ii) CCL (positive control) and iv) sham-ES (negative control). CES, CCL and sham-ES conditioning were delivered one week prior to nerve cut/coaptation. The conditioning site and the corresponding dorsal root ganglion neurons were harvest at 1 day, 3 days, and 14 days post-repair (n=10/cohort). Immunocytochemistry for macrophages and neurofilament to investigate inflammation and Wallerian degeneration respectively was performed. Data was corroborated by western blot analysis. CCR2-/- and RAG1-/- mice (n=3/cohort) were conditioned with CES to determine if monocytes or lymphocytes, respectively, are necessary to mount a conditioning effect and upregulate regeneration associated genes at the DRG.
Results: Rats treated with CCL alone at all time points evoked an inflammatory response. Unlike CES and sham-ES, there was significant macrophage infiltration at 1, 3, and 14 days following CCL at the conditioning site (p<0.001). Furthermore, although CCL induced Wallerian degeneration distal to the conditioning site, CES and sham-ES did not cause degeneration of the distal axons. The CES treated CCR2-/- and RAG1-/- mice both showed the same upregulation of pCREB (p<0.001) and ATF3 (p<0.001) as their corresponding C57/Bl wildtype mice, suggesting CES does not require the immune response to evoke the conditioning effect.
Conclusion: CES significantly improves regeneration and reinnervation beyond that attainable with current clinical standards. CES is a clinically feasible method of improving outcomes for patients with peripheral nerve injury as it does not evoke an inflammatory response or Wallerian degeneration. Further investigation is required to delineate the molecular and cellular mechanisms underlying the ability of CES to promote regeneration without evoking an immune response.
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