Erythropoietin Enhanced Recovery After Traumatic Nerve Injury: Myelination and Localized Effects.
OBJECTIVE
We previously found that administration of erythropoietin (EPO) shortens the course of recovery after experimental crush injury to the mouse sciatic nerve. The course of recovery was more rapid than would be expected if EPO's effects were caused by axonal regeneration, which raised the question of whether recovery was instead the result of promoting remyelination and/or preserving myelin on injured neurons. This study tested the hypothesis that EPO has a direct and local effect on myelination in vivo and in vitro.


METHODS
Animals were treated with EPO after standard calibrated sciatic nerve crush injury; immunohistochemical analysis was performed to assay for myelinated axons. Combined in vitro neuron-Schwann cell co-cultures were performed to assess EPO-mediated effects directly on myelination and putative protective effects against oxidative stress. In vivo local administration of EPO in a fibrin glue carrier was used to demonstrate early local effects of EPO treatment well in advance of possible neuroregenerative effects.


RESULTS
Systemic Administration of EPO maintained more in vivo myelinated axons at the site of nerve crush injury. In vitro, EPO treatment promoted myelin formation and protected myelin from the effects of nitric oxide exposure in co-cultures of Schwann cells and dorsal root ganglion neurons. In a novel, surgically applicable local treatment using Food and Drug Administration-approved fibrin glue as a vehicle, EPO was as effective as systemic EPO administration at time points earlier than those explainable using standard models of neuroregeneration.


CONCLUSIONS
In nerve crush injury, EPO may be exerting a primary influence on myelin status to promote functional recovery.


CONCLUSIONS
Mixed injury to myelin and axons may allow the opportunity for the repurposing of EPO for use as a myeloprotective agent in which injuries spare a requisite number of axons to allow early functional recovery.
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY.
Leigh
L
Sundem
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY.
Kuang-Ching
KC
Chris Tseng
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY.
Haiyan
H
Li
Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY.
John
J
Ketz
Department of Biomedical Genetics, Institute for Stem Cell and Regenerative Medicine, University of Rochester Medical Center, Rochester, NY.
Mark
M
Noble
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY. Electronic address: openelfar@gmail.com.
John
J
Elfar
D000818:Animals; D001707:Biopsy, Needle; D000071576:Crush Injuries / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D015552:Injections, Intralesional; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D011897:Random Allocation; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000187:drug effects* / Q000293:injuries*; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000473:pathology
D004921:Erythropoietin
Erythropoietin; functional recovery; peripheral nerve injury; regeneration