Ara 290: Mechanism of Action
1. Primary Receptor Target — The Innate Repair Receptor (IRR)
ARA-290 selectively binds to the Innate Repair Receptor (IRR), a heteromeric complex consisting of the erythropoietin receptor (EPOR) and the CD131 beta-common receptor (βcR). [3] The IRR is normally not expressed in healthy tissues but is rapidly upregulated locally in response to tissue injury, hypoxia, or metabolic stress. [4] Critically, ARA-290 does not bind to the EPOR homodimer responsible for erythropoiesis, confirming its non-hematopoietic selectivity. [2]
Swartjes et al. (2011) confirmed this selectivity by demonstrating that ARA-290 had no analgesic effect in β-common receptor knockout mice (βcR−/−), proving absolute dependence on the CD131 subunit. [3]
2. Downstream Signaling — JAK2 / STAT / PI3K / MAPK
Binding to the IRR initiates phosphorylation of Janus kinase 2 (JAK2), which propagates signal transduction through three principal pathways: [18]
- STAT Pathway: Activates STAT transcription factors to promote anti-apoptotic gene expression.
- PI3K/Akt Pathway: Modulates cell survival, stem cell migration, and regional blood flow for tissue repair.
- MAPK Pathway: Reduces inflammation, edema, and mediates anti-apoptosis.
ARA-290 also significantly inhibits NF-κB nuclear translocation, reducing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β) and increasing anti-inflammatory IL-10. [1]
3. Anti-Inflammatory and Neuroprotective Effects
In spinal cord tissue following nerve injury, ARA-290 suppresses microglia activation (reduced Iba-1 immunoreactivity) and astrocyte reactivity (reduced GFAP expression), shifting activated macrophages back to a resting phenotype. [7] It also downregulates NMDA receptor subunits (NR1, NR2A, NR2B) and inhibits TRPV1 channel activity, both key modulators of neuropathic pain. [7]
4. Cytoprotection and Mitochondrial Health
ARA-290 desensitizes the mitochondrial permeability transition pore (mPTP) to oxidant stress, significantly elevating the threshold for ROS-induced mPTP opening in cardiomyocytes. [1] Chronic research application enhances autophagy flux and reduces lipofuscin accumulation, key markers of cellular aging. [1]
5. "Molecular Switch" — Short Half-Life, Sustained Effects
Despite a very short plasma half-life (~2 minutes IV, ~20 minutes subcutaneous), ARA-290 triggers a "molecular switch" upon IRR activation. [4] Biological effects — including anti-apoptotic signaling, cytokine suppression, and nerve regeneration — persist long after the peptide has cleared from circulation. Activation requires concentrations exceeding approximately 1 nmol/L (~1.3 ng/mL). [5]
References
- Winicki NM, Nanavati AP, Morrell CH, et al. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med, 9, 1096887, 2023.
- Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. PNAS USA, 105(31), 10925–10930, 2008.
- Swartjes M, Morariu A, Niesters M, et al. ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain. Anesthesiology, 115(5), 1084–1092, 2011.
- Dahan A, Dunne A, Swartjes M, et al. ARA 290 improves symptoms in study subjects with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med, 19(1), 334–345, 2013.
- Brines M, Dunne AN, van Velzen M, et al. ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in study subjects with Type 2 Diabetes. Mol Med, 20(1), 658–666, 2015.
- Heij L, Niesters M, Swartjes M, et al. tolerability and efficacy of ARA 290 in sarcoidosis study subjects with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med, 18(1), 1430–1436, 2012.
- Swartjes M, van Velzen M, Niesters M, et al. ARA 290 produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain, 10, 13, 2014.
- McVicar CM, Hamilton R, Colhoun LM, et al. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes, 60(11), 2995–3005, 2011.
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide Improves Corneal Nerve Fiber Abundance in study subjects With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Invest Ophthalmol Vis Sci, 58(6), BIO52–BIO60, 2017.
- Lois N, Gardner E, McFarland M, et al. A Phase 2 Clinical Trial on the Use of Cibinetide for the investigation of Diabetic Macular Edema. J Clin Med, 9(7), 2225, 2020.
- Nairz M, Haschka D, Dichtl S, et al. Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep, 7(1), 13012, 2017.
- Collino M, Benetti E, Rogazzo M, et al. A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br J Pharmacol, 171(24), 5802–5815, 2014.
- Tokodai K, Brines M, Ericzon BG, et al. Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand. Transplantation, 104(10), 2020.
- Kumagai-Braesch M, Cerami A, Ericzon BG, et al. Cibinetide Protects Isolated Human Islets in a Stressful Environment. Cell Transplantation, 30, 2021.
- Schmidt RE, Feng D, Wang Q, et al. Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy in Akita diabetic mouse sympathetic ganglia. Exp Neurol, 232(2), 126–135, 2011.
- Niesters M, Swartjes M, Heij L, et al. The erythropoietin analog ARA 290 for investigation of sarcoidosis-induced chronic neuropathic pain. Expert Opin Orphan Drugs, 1, 77–87, 2013.
- Pulman KG, Smith M, Mengozzi M, et al. The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience, 233, 174–183, 2013.
- Brines M. Discovery of a Master Regulator of Injury and Healing: Tipping the Outcome from Damage toward Repair. Mol Med, 20(Suppl 1), S10–S16, 2014.
- Ahmet I, Tae H, Brines M, et al. Chronic administration of small nonerythropoietic peptide of erythropoietin ameliorates postmyocardial infarction-dilated cardiomyopathy. J Pharmacol Exp Ther, 345(3), 446–456, 2013.
- Coldewey SM, Khan AI, Kapoor A, et al. Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int, 84(3), 482–490, 2013.
- Muller C, Yassin K, Li LS, et al. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med, 21(1), 969–978, 2016.
Related Research Questions
Want the complete research review?
View Full Ara 290 Research Page→FOR RESEARCH USE ONLY
This content is provided for educational and informational purposes only. Products are furnished for in-vitro studies only and are not medicines, drugs, or supplements. Not approved by the FDA to prevent, treat, or cure any condition.