LOCAL ERYTHROPOIETIN SIGNALING ENHANCES REGENERATION IN PERIPHERAL AXONS

• Published in: Neuroscience Vol. 154; no. 2; pp. 767 - 783
• Main Authors: TOTH, C, MARTINEZ, J. A, LIU, W. Q, DIGGLE, J, GUO, G. F, RAMJI, N, MI, R, HOKE, A, ZOCHODNE, D. W
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 23.06.2008
• Subjects: Animals; Axons - drug effects; Behavior, Animal - drug effects; Biological and medical sciences; Blotting, Western; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Electrophysiology; Erythropoietin - pharmacology; Fundamental and applied biological sciences. Psychology; Ganglia, Spinal - drug effects; Ganglia, Spinal - pathology; Hand Strength; Immunohistochemistry; Male; Nerve Crush; Nerve Regeneration - drug effects; Neural Conduction - drug effects; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Sciatic Nerve - injuries; Sciatic Nerve - pathology; Sciatic Nerve - physiology; Signal Transduction - drug effects; Spinal Cord - physiology; Vertebrates: nervous system and sense organs; Regeneration; Signal transduction; erythropoietin receptor; Erythropoietin; nerve injury; Axon; nerve regeneration; Lesion; Biological receptor
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.03.052

Erythropoietin (EPO) and its receptor (EPO-R), mediate neuroprotection from axonopathy and apoptosis in the peripheral nervous system (PNS). We examined the impact and potential mechanisms of local EPO signaling on regenerating PNS axons in vivo and in vitro. As a consequence of injury, peripheral nerve axons and DRG neurons have a marked increase in the expression of EPO and EPO-R. Local delivery of EPO via conduit over 2 weeks to rat sciatic nerve following crush injury increased the density and maturity of regenerating myelinated axons growing distally from the crush site. In addition, EPO also rescued retrograde degeneration and atrophy of axons. EPO substantially increased the density and intensity of calcitonin gene-related peptide (CGRP) expression within outgrowing axons. Behavioral improvements in sensorimotor function also occurred in rats exposed to near nerve EPO delivery. EPO delivery led to decreased nuclear factor kappaB (NFkB) activation but increased phosphorylation of Akt and STAT3 within nerve and dorsal root ganglia neurons indicating rescue from an injury phenotype. Spinal cord explant studies also demonstrated a similar dose-dependent effect of EPO upon motor axonal outgrowth. Local EPO signaling enhances regenerating peripheral nervous system axons in addition to its known neuroprotection. Exogenous EPO may have a therapeutic role in a large number of peripheral nerve diseases through its impact on regeneration.