Neuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological... Show moreNeuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological treatment is often inadequate and coincides with intolerable side effects. The spared nerve injury animal model of neuropathic pain was employed as a method for evaluating the effect of the 11-amino acid tissue protective peptide ARA 290, and the NMDA receptor antagonist ketamine on behavioral and cellular responses after nerve injury and comparison of these two drugs. Clinically, pain is a subjective outcome that can be measured by numerical rating scales or questionnaires. Due to this subjectiveness it is not reliable for diagnosing small fiber neuropathy (SFN). Therefore, SFN is being diagnosed by invasive method of intra-epidermal nerve fiber density evaluated with microscopy. Alternatively, the cornea has a high density of small nerve fibers that can be evaluated by the non-invasive method of corneal confocal microscopy. Finally, the effect of ARA 290 on nerve fiber loss and corneal nerve fiber density in sarcoidosis patients in a double-blind-randomized clinical study was evaluated that showed that ARA 290 is a potential disease modifying agent for treatment of sarcoidosis-associated SNFLD. Show less
Swartjes, M.; Velzen, M. van; Niesters, M.; Aarts, L.; Brines, M.; Dunne, A.; ... ; Dahan, A. 2014
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... Show moreBACKGROUND: 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. Show less
Dahan, A.; Dunne, A.; Swartjes, M.; Proto, P.L.; Heij, L.; Vogels, O.; ... ; Brines, M. 2013
ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models... Show moreARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ≥5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (Δ -11.5 ± 3.04 versus Δ -2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (Δ -23.4 ± 5.5 and Δ -14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms. Show less
Swartjes, M.; Niesters, M.; Heij, L.; Dunne, A.; Aarts, L.; Hand, C.C.; ... ; Dahan, A. 2013
