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Determining the mechanism through which conditioning electrical stimulation promotes nerve regeneration
Christine A Webber, PhD1, Leah Acton, BSc2, K. Ming Chan, MD, FRCPC3 and Jenna-Lynn Senger, MD PhD1, (1)University of Alberta, Edmonton, AB, Canada, (2)Univeristy of Alberta, Edmonton, AB, Canada, (3)Department of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, AB, Canada

Background: Functional recovery following injury is largely attributable to the time required for target reinnervation given the slow speed of axonal growth. Lifelong sensorimotor deficits, particularly among patients with proximal nerve injuries, may preclude independent daily living; thus, accelerating axon extension has significant clinical importance. Conditioning crush lesion (CCL), in which a crush injury is performed one week prior to nerve transection and repair, increases the rate of nerve growth, however it is not clinically feasible as it requires an intentional nerve injury and evokes an inflammatory response. We have demonstrated that conditioning electrical stimulation (CES) accelerates nerve regeneration and promote sensorimotor functional recovery similar to CCL. This study compares the mechanisms through which CES and CCL promote nerve regeneration.

Methods: In a Sprague-Dawley rat and 2 mice models, we compared a) how CES and CCL upregulate regeneration associated genes (RAGs), b) which RAG expression is involved in each response, and c) the role of inflammation in mediating the effects of CCL and CES. Animals were treated with either CES or CCL to their tibial nerves; seven days later the dorsal root ganglia (DRG) were harvested.

Results: Comparable to CCL, which is well-described to activate cAMP signalling and block the PTEN pathway, CES was found to activate RhoA GTPases to upregulate RAG expression at the DRG. This suggests a common pathway through which CES and CCL evoke their conditioning effects at the DRG. Our tissue analysis further demonstrated that CCL and CES similarly upregulate the RAGs brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43), and phosphorylated-cyclic adenosine monophosphate response elements binding protein (p-CREB), indicating an enhanced regenerative response. The injury marker activation transcription factor 3 (ATF-3), however, was only expressed in the CCL cohort, supporting our hypothesis that CES is non-injurious. One week following tibial nerve conditioning, adult Sprague-Dawley rat and C57/bl mice upregulate CD68 and IBA macrophage/monocyte markers following CCL but not CES. Cx3CR1CreER;Ai9 mice which fluorescently labels tissue resident macrophages to distinguish them from blood-infiltrating monocytes show that one week following tibial nerve conditioning, CES and CCL have a comparable upregulation of tissue resident macrophages at the DRG.
Conclusions: Conditioning with CES or CCL likely act through a common pathway to promote nerve regeneration via upregulation of RAGs potentially through the RhoA GTPase pathway, and by activation of DRG tissue resident macrophages. Unlike CCL, CES is non-injurious and non-inflammatory, suggesting greater acceptability for adoption into the clinical setting.

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