ARA-290 16mg

▎ARA-290 Structure

▎ARA-290 Research

What is the research background of ARA-290?  

The development of ARA-290 originated from exploring the therapeutic potential of erythropoietin (EPO). Scientists found that EPO not only promotes erythropoiesis but also has tissue-protective functions such as anti-inflammation and anti-apoptosis. However, EPO’s hematopoietic stimulation may increase blood viscosity and other risks, limiting its use in treating non-anemic diseases. To retain EPO’s tissue-protective effects while avoiding its hematopoietic side effects, researchers began designing derivative peptides, leading to the creation of ARA-290.  

With deeper research, the unique advantages of ARA-290 as a non-hematopoietic peptide were gradually recognized. It activates anti-inflammatory and tissue repair signaling pathways by binding to the innate repair receptor (IRR), demonstrating promising effects in treating diabetic complications, neuropathies, and renal injuries. These findings laid the foundation for further research and clinical applications of ARA-290 and promoted the development of novel therapeutic strategies based on EPO-derived peptides.  

What is the mechanism of action of ARA-290?  

Anti-Inflammatory Effect: ARA-290 inhibits the secretion of inflammatory cytokines, thereby reducing inflammatory responses, as demonstrated in multiple disease models. For example, in a mouse model of systemic lupus erythematosus (SLE), it reduces serum concentrations of inflammatory cytokines IL-6, MCP-1, and TNF-α, improving SLE symptoms{#Dahan, A,2016} (Dahan A, 2016). In a cisplatin-induced nephrotoxicity model, it decreases pro-inflammatory cytokines TNFα, IL6, and IL1β, alleviating renal inflammation ^[2](Ghassemi-Barghi N, 2023). Its anti-inflammatory mechanism may involve targeting the innate repair receptor (IRR), a heterodimer of the erythropoietin receptor and β-common (CD131) receptor. Binding to IRR activates downstream anti-inflammatory signaling pathways, thereby downregulating inflammation^[1].

Anti-Apoptotic Effect: ARA-290 inhibits cell apoptosis and promotes tissue cell survival. In a diabetic rat model, it suppresses renal tubular epithelial cell apoptosis and reduces the expression of key proteases in the apoptotic process, thereby exerting renal protective effects. In cisplatin-induced nephrotoxicity models, it regulates the expression of apoptosis-related proteins such as Bax and Bcl-2, inhibits Caspase-3 activity, reduces cell apoptosis, and mitigates cisplatin-induced renal cell damage^[2].  

Anti-Oxidative Effect: ARA-290 inhibits oxidative stress damage and reduces the production of harmful substances such as reactive oxygen species (ROS). In a diabetic rat kidney model, it suppresses renal gene expression, reduces renal ROS levels, and decreases malondialdehyde (MDA) expression, alleviating oxidative stress-induced renal damage. In atherosclerosis studies, in vitro experiments show that ARA-290 inhibits ROS production in macrophages under inflammatory conditions, reducing oxidative stress damage to cells.  

Regulation of Immune Cell Function: ARA-290 regulates the function of immune cells such as macrophages. In vitro, it inhibits inflammatory activation of macrophages while promoting their phagocytic function toward apoptotic cells, helping maintain immune system homeostasis and clear apoptotic cells to avoid inflammation caused by their accumulation (Dahan A, 2016). In atherosclerosis research, ARA-290 inhibits macrophage migration and foam cell formation, reducing lipid deposition in the vascular intima and slowing atherosclerosis progression.

Neuroprotective Mechanism: In a mouse model of cerebral ischemia, ARA-290 exerts neuroprotective effects through the β-common receptor (βCR). It significantly reduces neuronal apoptosis and inflammatory cytokine levels in brain tissue, improving neurological function. Injection of βCR-targeted siRNA significantly inhibits ARA-290’s neuroprotective effects, indicating that βCR plays a key role in its mechanism^[3].  

Analgesic Mechanism: ARA-290 may exert analgesic effects by directly targeting peripheral nociceptors. Studies show it specifically inhibits TRPV1 channel activity and alleviates capsaicin-induced mechanical allodynia, suggesting ARA-290 may serve as a novel TRPV1 channel antagonist, providing new insights for pain treatment ^[4].  

What are the applications of ARA-290?

Treatment of Neuropathies

Pain Relief and Symptom Improvement: ARA-290 effectively relieves neuropathic pain, particularly in diseases with neuropathy such as diabetes and sarcoidosis. In clinical trials for sarcoidosis patients, ARA-290 significantly improved neuropathy and autonomic nerve symptoms, enhanced quality of life, and reduced pain scores, with similar effects in diabetic neuropathy patients. Its mechanism involves binding to the innate repair receptor (IRR), activating anti-inflammatory and tissue repair pathways, regulating neurogenic inflammation, and alleviating pain ^{[1, 4]}.

Promotion of Nerve Fiber Regeneration: ARA-290 promotes nerve fiber regeneration. In sarcoidosis patients, 28 consecutive days of ARA-290 treatment induced corneal small nerve fiber regeneration, demonstrating repair capacity for specific nerve fibers and potential to improve neurological function, although it had no effect on epidermal nerve fibers ^[1].  

Reduction of Nephrotoxicity  

Decreased Cytotoxicity and Genotoxicity: In cisplatin-induced nephrotoxicity models, ARA-290 significantly reduces cisplatin-induced cytotoxicity and genotoxicity, such as decreasing DNA damage parameters in comet assays and micronucleus frequency, protecting cellular genetic material and mitigating renal cell damage^[1].

Regulation of Oxidative Stress and Inflammation: ARA-290 improves cisplatin-induced oxidative stress by reducing malondialdehyde (MDA) and ROS levels and enhancing antioxidant enzyme activity. It also alleviates renal inflammation by decreasing pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β), protecting against cisplatin-induced renal injury^[1] .  

Inhibition of Apoptosis: ARA-290 inhibits cisplatin-induced apoptosis by regulating apoptosis-related genes and proteins (e.g., decreasing Caspase-3 and Bax expression, increasing Bcl-2 expression), maintaining renal cell survival and holding potential for treating acute kidney injury patients ^[1].  

Improvement of Depressive Symptoms  

Alleviation of Depression-Like Behavior: In mouse models of chronic unpredictable mild stress and chronic social defeat stress, daily ARA-290 administration improved depression-like behavior, comparable to the common antidepressant fluoxetine. ARA-290 exerted antidepressant effects without significantly affecting peripheral hemoglobin or red blood cells ^[5].  

Regulation of Immune Cells and Inflammation: ARA-290 reverses chronic stress-induced increases in the frequency and number of CD11b⁺Ly6Ghi neutrophils and CD11b⁺Ly6Chi monocytes in bone marrow and meninges, as well as microglial activation, alleviating depressive symptoms through anti-inflammatory effects and providing new treatment pathways for depression ^[5].  

Protection Against Diabetic Kidney Damage  

Inhibition of Renal Tubular Epithelial Apoptosis: ARA-290 inhibits renal tubular epithelial cell apoptosis, reducing programmed cell death and protecting renal cells.  

Improvement of Renal Function Markers: ARA-290 decreases urinary albumin excretion rate in diabetic rats, alleviates renal pathological damage, improves renal function, and delays diabetic nephropathy progression.  

Treatment of Systemic Lupus Erythematosus (SLE)  

Inhibition of Autoantibody Production and Immune Complex Deposition: ARA-290 significantly inhibits serum antinuclear antibody (ANA) and anti-double-stranded DNA antibody levels in induced SLE mice, reduces IgG and C3 deposition in kidneys, alleviates nephritis symptoms, and improves disease progression ^[6].  

Figure 1 ARA290 treatment suppressed inflammatory response in pristane‐induced SLE mice. (A) The levels of IL‐6, IL‐10, MCP‐1, IFN‐γ, TNF‐α, IL‐12p70 and TGF‐β in the serum following treatment described in Figure 1 were detected (n = 6). (B) The inflammatory macrophage F4/80 infiltration was significantly suppressed by ARA 290 intervention compared to PBS control. (C) The spleen and lymph node weights were measured following ARA290 treating in SLE mice (n = 6). Scale bars represent 30 μm.

Source:PubMed^[6]

Reduction of Inflammatory Cytokine Levels: ARA-290 decreases serum concentrations of inflammatory cytokines IL-6, MCP-1, and TNF-α in SLE mice, reducing inflammation and alleviating disease symptoms ^[6].  

Decreased Apoptosis: ARA-290 reduces the number of apoptotic cells in kidneys, protects renal cells, and inhibits inflammatory activation of macrophages while promoting their phagocytosis of apoptotic cells in vitro, regulating the immune system and holding potential for SLE treatment ^[6].  

Mitigation of Chemotherapeutic Drug Toxicity  

Reduction of DNA Damage: In doxorubicin (DOX)-induced cytotoxicity models, ARA-290 significantly reduces DOX-induced DNA damage, such as decreasing tail DNA percentage in comet assays and micronucleus frequency, protecting cellular genetic material and reducing chemotherapeutic damage to normal cells ^[7].  

Alleviation of Oxidative Stress and Inflammation: ARA-290 mitigates DOX-induced impairment of antioxidant enzyme activity, reduces inflammation and apoptosis, and protects against DOX-induced oxidative stress and cell damage, potentially including cardiac cells, to alleviate adverse effects in chemotherapy patients ^[7].  

Prevention and Treatment of Alzheimer’s Disease  

Slowed Pathological Progression and Improved Cognition: Early administration of ARA-290 in young APP/PS1 mice (early Alzheimer’s model) slows β-amyloid (Aβ) pathological progression and improves cognitive function, highlighting its significance for early intervention^[8].

Regulation of Monocyte Function: ARA-290 specifically stimulates the generation of Ly6C⁻ patrolling monocyte subsets, increases their circulating levels, promotes Aβ clearance from cerebral blood vessels, reduces brain Aβ burden, and delays disease progression. However, it is less effective in late-stage models (aged APP/PS1 mice), underscoring the importance of early intervention ^[8].  

Promotion of Diabetic Wound Healing

Accelerated Wound Closure: In streptozotocin-induced diabetic incisional wound rat models, local ARA-290 application significantly accelerates wound closure, shortens reepithelialization time, and improves wound healing efficiency^[9] .  

Regulation of Tissue Repair Markers: ARA-290 increases collagen and protein content in repair tissues, regulates serum insulin, blood glucose, lipid levels, antioxidant status, and pro-inflammatory cytokine levels, creating a microenvironment conducive to wound healing and providing new strategies for treating diabetic foot ulcers ^[9].  

Pain Relief  

Inhibition of TRPV1 Channel Activity: ARA-290 relieves capsaicin-induced mechanical allodynia by inhibiting transient receptor potential vanilloid subtype 1 (TRPV1) channel activity, directly targeting peripheral nociceptors and providing new therapeutic targets and approaches for pain treatment ^[4].  

Conclusion  

ARA-290 is an EPO-derived polypeptide with anti-inflammatory, anti-apoptotic, and anti-oxidative effects. It can treat pain in diabetes and sarcoidosis, promote nerve fiber regeneration, combat nephrotoxicity, SLE, depression, and alleviate pain by antagonizing TRPV1. With potential in early Alzheimer’s intervention and other fields, it holds broad clinical application prospects.

About The Author

The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.

Scientific Journal Author

Al-Onaizi, Mohammed is a scholar with deep expertise in the field of biomedicine. He has close ties with several renowned academic and research institutions, including Dasman Diabetes Institute (DDI), Kuwait University, Laval University, Western University (University of Western Ontario), and Hebrew University of Jerusalem. His research interests are broad, covering Neurosciences & Neurology, Biochemistry & Molecular Biology, Immunology, Psychiatry, and other topics in Life Sciences & Biomedicine. These disciplines are crucial for gaining a deeper understanding of human physiological mechanisms, disease processes, and the development of new treatments. Al-Onaizi, Mohammed's research has achieved significant results in basic sciences and has provided vital theoretical support and practical guidance for clinical medicine and biomedical research.. Al-Onaizi, Mohammed is listed in the reference of citation [8].

▎Relevant Citations

[1]  Dahan A, Brines M, Niesters M, et al. Targeting the innate repair receptor to treat neuropathy[J]. Pain Reports, 2016,1(1):e566.DOI:10.1097/PR9.0000000000000566.

[2]   Ghassemi-Barghi N, Ehsanfar Z, Mohammadrezakhani O, et al. Mechanistic Approach for Protective Effect of ARA290, a Specific Ligand for the  Erythropoietin/CD131 Heteroreceptor, against Cisplatin-Induced Nephrotoxicity,  the Involvement of Apoptosis and Inflammation Pathways[J]. Inflammation, 2023,46(1):342-358.DOI:10.1007/s10753-022-01737-7.

[3]   Wang R, Yang Z, Huang Y, et al. Erythropoietin‐derived peptide ARA290 mediates brain tissue protection through the $\beta$‐common receptor in mice with cerebral ischemic stroke[J]. CNS Neuroscience \& Therapeutics, 2024,30. https://api.semanticscholar.org/CorpusID:268414491.

[4]   Zhang W, Yu G, Zhang M. ARA 290 relieves pathophysiological pain by targeting TRPV1 channel: Integration  between immune system and nociception[J]. Peptides, 2016,76:73-79.DOI:10.1016/j.peptides.2016.01.003.

[5]   Xu G, Zou T, Deng L, et al. Nonerythropoietic Erythropoietin Mimetic Peptide ARA290 Ameliorates Chronic  Stress-Induced Depression-Like Behavior and Inflammation in Mice[J]. Frontiers in Pharmacology, 2022,13:896601.

DOI:10.3389/fphar.2022.896601.

[6]   Huang B, Jiang J, Luo B, et al. Non-erythropoietic erythropoietin-derived peptide protects mice from systemic  lupus erythematosus[J]. Journal of Cellular and Molecular Medicine, 2018,22(7):3330-3339.DOI:10.1111/jcmm.13608.

[7]   Shokrzadeh M, Etebari M, Ghassemi-Barghi N. An engineered non-erythropoietic erythropoietin-derived peptide, ARA290,  attenuates doxorubicin induced genotoxicity and oxidative stress[J]. Toxicology in Vitro, 2020,66:104864.

DOI:10.1016/j.tiv.2020.104864.

[8]   Al-Onaizi M A, Thériault P, Lecordier S, et al. Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates  AD-like pathology progression[J]. Brain Behavior and Immunity, 2022,99:363-382.

DOI:10.1016/j.bbi.2021.07.016.

[9]   Mashreghi M, Bayrami Z, Sichani N, et al. An in vivo investigation on the wound-healing activity of Specific ligand for the innate repair receptor, ARA290, using a diabetic animal model[M]. 2023.DOI:10.21203/rs.3.rs-2520194/v1.

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