title: ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response.
abstract: BACKGROUND
  Neuropathic pain is a difficult to treat disorder arising from central or peripheral nervous system lesions. The etiology of neuropathic pain consists of several overlapping pathways converging into an exaggerated pain state with symptoms such as allodynia and hyperalgesia. One of these pathways involves activation of spinal cord microglia and astrocytes, which drive and maintain the inflammatory response following the lesion. These cells are a potential target for drugs for neuropathic pain relief. In this current study, we investigated the dose-effect relationship of the tissue protective peptide ARA 290, derived from the tertiary structure of erythropoietin, on allodynia and concurrent spinal cord microglia and astrocytes.
  
  
  RESULTS
  Following a spared nerve injury in rats, vehicle or ARA290 (administered in either one of 4 doses: 3, 10, 30 and 60 μg/kg) was administered on days 1, 3, 6, 8 and 10. ARA290 exerted a dose-response effect by significantly reducing mechanical allodynia up to 20 weeks when compared to vehicle. The reduction of cold allodynia was significant up to 20 weeks for the doses 3, 10, 30 and 60 μg/kg when compared to vehicle. The effect 10 and 30 μg/kg ARA290 and vehicle on the microglia response (iba-1-immunoreactivity, iba-1-IR) and astrocyte reaction (GFAP-immunoreactivity, GFAP-IR) was investigated in animals surviving 2 (group 1) or 20 (group 2) weeks following lesion or sham surgery. In group 1, significant microglia reactivity was observed in the L5 segment of the spinal cord of animals treated with vehicle when compared to sham operated, while animals treated with 10 or 30 μg/kg did not show a increase. In group 2, a more widespread and increased microglia reactivity was observed for animals treated with 0 and 10 μg/kg when compared to sham operated animals, indicated by involvement of more spinal cord segments and higher iba-1-IR. Animals treated with 30 μg/kg did not show increased microglia reactivity. No difference in astrocyte reaction was observed.
  
  
  CONCLUSIONS
  The erythropoietin-analogue ARA290 dose-dependently reduced allodynia coupled to suppression of the spinal microglia response, suggestive of a mechanistic link between ARA290-induced suppression of central inflammation and relief of neuropathic pain symptoms.
authors: Maarten
authors: M
authors: Swartjes
authors: Monique
authors: M
authors: van Velzen
authors: Marieke
authors: M
authors: Niesters
authors: Leon
authors: L
authors: Aarts
authors: Michael
authors: M
authors: Brines
authors: Ann
authors: A
authors: Dunne
authors: Anthony
authors: A
authors: Cerami
authors: Department of Anesthesiology, Leiden University Medical Center, P5-Q, 2300 RC Leiden, The Netherlands. a.dahan@lumc.nl.
authors: Albert
authors: A
authors: Dahan
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000737:chemistry*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009842:Oligopeptides; D004921:Erythropoietin; C576178:cibinetide