Erythropoietin reduces Schwann cell TNF-alpha, Wallerian degeneration and pain-related behaviors after peripheral nerve injury.
Chronic sciatic nerve constriction injury (CCI) induces Wallerian degeneration and exaggerated pain-like behaviors. These effects are mediated in large part by pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha). In this study, we demonstrate that systemically administered recombinant human erythropoietin (rhEpo) facilitates recovery from chronic neuropathic pain associated with CCI in rats. Because TNF-alpha has been implicated in the development of pain-related behaviors, we measured TNF-alpha mRNA at the nerve injury site. Systemically or locally administered rhEpo decreased TNF-alpha mRNA, compared with that observed in untreated animals. RhEpo also significantly (P < 0.05) decreased axonal degeneration. Immunohistochemistry of CCI nerve showed abundant TNF-alpha in Schwann cells, axoplasm and macrophages. In rhEpo-treated animals, TNF-alpha immunopositivity was decreased selectively in Schwann cells. These results suggest a model in which rhEpo counteracts the effects of TNF-alpha in CCI by blocking expression of TNF-alpha in Schwann cells. To further test this model, we studied primary Schwann cell cultures. RhEpo inhibited TNF-alpha expression in response to lipopolysaccharide, supporting the conclusions of our in vivo CCI experiments. In addition, rhEpo directly counteracted Schwann cell death induced by exogenously added TNF-alphain vitro. These results indicated that rhEpo regulates TNF-alpha by multiple mechanisms; rhEpo regulates TNF-alpha mRNA expression by Schwann cells but also may directly counteract TNF-alpha signaling pathways that lead to injury, chronic pain and/or death.
Campana
W Marie
WM
Department of Anesthesiology, University of California, San Diego School of Medicine, La Jolla, CA, USA. wcampana@ucsd.edu
Li
Xiaoqing
X
Shubayev
Veronica I
VI
Angert
Mila
M
Cai
Karen
K
Myers
Robert R
RR
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001794:Blood Pressure / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D053331:Ectodysplasins; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006400:Hematocrit / Q000379:methods; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007150:Immunohistochemistry / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D014855:Wallerian Degeneration / Q000188:drug therapy* / Q000209:etiology
C506018:EDA protein, human; D053331:Ectodysplasins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D004921:Erythropoietin