Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury.
Erythropoietin (Epo) has been shown to have potent anti-apoptotic activity in central nervous system neurons in animal models of ischaemic injury. Recently, Epo and its receptor (EpoR) have been identified in the peripheral nervous system [Campana & Myers (2001), FASEB J., 15, 1804-1806]. Herein, we demonstrate that in painful neuropathy caused by L5 spinal nerve crush (SNC), therapy with recombinant human Epo (rhEpo) reduced dorsal root ganglion (DRG) apoptosis and pain behaviours. Quantification of both DRG neurons and satellite cells revealed that vehicle-treated, crush-injured DRGs had 35.5 +/- 8.3% apoptotic neurons and 23.5 +/- 2.36% satellite cells compared with 7.5 +/- 6.3% apoptotic neurons and 6.4 +/- 3.94% satellite cells in rhEpo-treated, crush-injured DRGs (P < 0.05). While rhEpo-treated animals were not initially protected from mechanical allodynia associated with L5 SNC, rhEpo did significantly improve recovery rates compared to vehicle-treated animals (P < 0.01). Systemic rhEpo therapy increased JAK2 phosphorylation, a key anti-apoptotic signalling molecule for Epo-induced neuroprotection, in DRGs after crush. Dual immunofluorescence demonstrated Epo-induced JAK2-p was associated with both neuronal and glial cells. JAK2-p was associated with NF200-positive large neurons and with smaller neurons. This population of small neurons did not colocalize with IB4, a marker of nonpeptidergic, glial derived growth factor-responsive neurons. The findings link anti-apoptosis activities of Epo/EpoR/JAK2 in DRG neurons capable of inducing protracted pain states with reductions in pain behaviours, and therefore support a role for Epo therapy in the treatment of neuropathic pain.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal; D015153:Blotting, Western; D002232:Carbocyanines / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D005455:Fluorescent Antibody Technique; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia; D020287:In Situ Nick-End Labeling; D053614:Janus Kinase 2; D018613:Microscopy, Confocal; D016900:Neurofilament Proteins / Q000378:metabolism; D010146:Pain / Q000473:pathology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D037121:Plant Lectins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D054788:Ribosome Inactivating Proteins; D027161:Satellite Cells, Perineuronal / Q000378:metabolism; D013997:Time Factors
D002232:Carbocyanines; D005904:Glial Fibrillary Acidic Protein; D016900:Neurofilament Proteins; D037121:Plant Lectins; D011518:Proto-Oncogene Proteins; C050600:Sambucus nigra lectins; C098830:TO-PRO-3; C051774:neurofilament protein H; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D054788:Ribosome Inactivating Proteins