Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy
Journal
GLIA
Journal Volume
66
Journal Issue
11
Pages
2299-2315
Date Issued
2018
Author(s)
Abstract
Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation. Enzyme-linked immunosorbent assay and microdialysis were applied to measure pro-inflammatory cytokine and glutamate responses, respectively. EPO pre-treatment dose-dependently ameliorated neuropathic pain behavior, decreased microglial and MAPKs activation, and diminished the release of pro-inflammatory cytokines and glutamate in the ipsilateral cuneate nucleus after CCI. Moreover, EPO pre-treatment preserved myelination of the injured median nerve on morphological investigation and suppressed injury-induced discharges. We also observed that EPO receptor (EPOR) expression was up-regulated in the injured nerve after CCI. Double immunofluorescence showed that EPOR was localized to Schwann cells. Furthermore, siRNA-mediated knockdown of EPOR expression eliminated the therapeutic effects of EPO on attenuating the microglial and MAPKs activation, pro-inflammatory cytokine responses, injury discharges, and neuropathic pain behavior in CCI rats. In conclusion, binding of EPO to its receptors on Schwann cells maintains myelin integrity and blocks ectopic discharges in the injured median nerve, that in the end contribute to attenuation of neuropathic pain via reducing glutamate release from primary afferents and inhibiting activation of microglial MAPKs and production of pro-inflammatory cytokines. ? 2018 Wiley Periodicals, Inc.
SDGs
Other Subjects
erythropoietin; erythropoietin receptor; mitogen activated protein kinase p38; myelin; small interfering RNA; cytokine; erythropoietin; erythropoietin receptor; mitogen activated protein kinase kinase; small interfering RNA; animal experiment; animal model; Article; chronic constriction injury; controlled study; cuneate nucleus; cytokine response; demyelination; electrophysiology; enzyme activation; enzyme linked immunosorbent assay; enzyme phosphorylation; human; hyperalgesia; immunofluorescence; immunohistochemistry; median nerve; microdialysis; microglia; neuropathic pain; nonhuman; peripheral nerve injury; peripheral neuropathy; priority journal; qualitative analysis; quantitative analysis; rat; real time polymerase chain reaction; Schwann cell; therapy effect; action potential; animal; complication; disease model; drug effect; gene expression regulation; genetics; hyperalgesia; male; metabolism; microglia; neuralgia; pain threshold; pathology; peripheral neuropathy; phosphorylation; polyradiculoneuropathy; Schwann cell; signal transduction; Sprague Dawley rat; Action Potentials; Animals; Cytokines; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Hyperalgesia; Male; Median Nerve; Microglia; Mitogen-Activated Protein Kinase Kinases; Neuralgia; Pain Threshold; Peripheral Nervous System Diseases; Phosphorylation; Polyradiculoneuropathy; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; RNA, Small Interfering; Schwann Cells; Signal Transduction
Publisher
John Wiley and Sons Inc.
Type
journal article