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

作者：Swartjes Maarten; van Velzen Monique; Niesters Marieke; Aarts Leon; Brines Michael; Dunne Ann; Cerami Anthony; Dahan Albert^*

来源：Molecular Pain, 2014, 10: 13.

DOI：10.1186/1744-8069-10-13

• ARA 290
• Spared nerve injury
• Allodynia
• Dorsal horn
• Microglia
• Iba-1
• Astrocytes
• GFAP

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 mu g/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 mu g/kg when compared to vehicle. The effect 10 and 30 mu g/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 mu g/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 mu g/kg when compared to sham operated animals, indicated by involvement of more spinal cord segments and higher iba-1-IR. Animals treated with 30 mu g/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.

• 出版日期2014-2-16