Studies suggest that ARA 290 may dampen the upregulation of the spinal inflammatory mediator CCL2, as well as the markers Iba-1 and GFAP, as well as the NMDA receptor subunits (NR1, NR2A, and NR2B) that were caused by nerve injury. All of the measurements taken were based on gene expression, which suggests that ARA 290 might have affected the inflammatory response that involved both microglia and astrocytes.
Researchers noted that “These experimental … studies suggest that ARA 290 may effectively reprogram a pro-inflammatory, tissue-damaging milieu into one of healing and tissue repair.” It has been suggested that ARA 290, a nonhematopoietic erythropoietin analog, may inhibit the activation of macrophages and prevent damage to transplanted platelets. The intrahepatic inflammatory responses that occur after PITx are speculated to be inhibited by ARA 290.
The findings implied that the islets appeared to be protected against cytokine-induced damage and apoptosis by having ARA 290 present. It was hypothesized that ARA 290 may substantially impact the inhibition of the secretion of pro-inflammatory cytokines (IL-6, IL-12, and TNF-α) from macrophages. Once the minimal PITx was given, the presentation of ARA 290 seemed to have resulted in a substantial improvement in blood glucose levels compared to control animals. Within the liver, the presentation with ARA 290 appeared to effectively suppress the upregulation of messenger RNA expression for monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, interleukin-1β, and interleukin-6.
ARA-290 Peptide and Microglia Activity
The potential of ARA 290 and vehicle on the microglia response (iba-1-immunoreactivity, iba-1-IR) and astrocyte reaction (GFAP-immunoreactivity, GFAP-IR) were examined in rats that survived two weeks (group 1) or twenty weeks (group 2) after undergoing lesion or sham surgery. In the first group, animals presented with vehicles suggested a substantial increase in microglial reactivity in the L5 section of the spinal cord compared to animals given sham surgery.
On the other hand, animals that were presented with different concentrations did not report any increase. In group 2, a more extensive and enhanced microglia reactivity was identified for animals with lower concentrations than animals subjected to a sham operation. The participation of a greater number of spinal cord segments and a higher iba-1 inhibitory receptor suggested this. However, no sign of enhanced microglia reactivity in animals given higher concentrations. It was speculated that there was no change in the astrocyte response.
The erythropoietin-analog ARA 290 was theorized to have diminished allodynia concentration-dependently, reducing the spinal microglia response. This finding suggests a mechanical connection between the suppression of central inflammation that ARA 290 might induce and the alleviation of neuropathic pain sensations.
During diabetic retinopathy, intervention with a peptide derived from erythropoietin protects against neuroglial and vascular deterioration; scientists speculated: “pHBSP regulates microglial activation and cytokine expression in the diabetic retina.”
When compared with diabetic rats presented with the scrambled pHBSP, the exposure to pHBSP did not affect the total number of microglia. However, this resulted in a substantial increase in the percentage of cells with a dendritic phenotype and a reduction in the number of amoeboid cells. Lectin-stained microglia also demonstrated that diabetes was linked to an increase in microglia in the inner plexus of the central retina and peripheral retina compared to the controls.
ARA 290 Peptide and Macrophages
There is a correlation between the clearance of damaged tissue and the promotion of immunological tolerance and kidney healing. Consequently, enhancing phagocytosis of macrophages is believed to be one of the mechanisms contributing to the renoprotective action of EPO. A concept of this kind does not contradict the findings of the research, which focused on the functional flip of macrophages.
In vitro experiments are the most common method for defining macrophage activation. There are two major subtypes of macrophage activation: classically activated M1 macrophages are pro-inflammatory and deleterious in sterile tissue injuries.
Conversely, activated M2 macrophages are characterized by their immunoregulatory and tissue repair capabilities. This key categorization, although somewhat straightforward, is widely recognized and explains the functional flexibility and dynamics of macrophages in response to various stressors. Generally speaking, renal macrophages are a diverse group, and their phenotypes may shift depending on the physiological and pathological situations they are exposed to.
It is only possible for EPO to suppress apoptosis; it is not capable of inhibiting necroptosis, which is more damaging and pro-inflammatory. Conversely, the EPO reduces the amount of the chemokine CCL7 that is released, inhibiting the migration of monocytes into the kidneys. A further benefit of EPO is that it can directly block the activation of M1 subtypes and encourage polarization toward M2 phenotypes. Consequently, the M1/M2 ratio is positively regulated toward an anti-inflammatory phenotype during rhabdomyolysis-induced acute kidney injury, which in turn may help to alleviate the renal damage.
Visit corepeptides.com if you are a researcher interested in further studying ARA 290. Please note that none of the substances mentioned in this article have been approved for human consumption.
References
[i] Dahan, Albert, et al. “Targeting the Innate Repair Receptor to Treat Neuropathy.” Pain Reports, vol. 1, no. 1, 9 Aug. 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741312/ 10.1097/PR9.0000000000000566.
[ii] Swartjes, Maarten, et al. “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.” Molecular Pain, vol. 10, 16 Feb. 2014, p. 13, www.ncbi.nlm.nih.gov/pmc/articles/PMC3928087/, 10.1186/1744-8069-10-13.
[iii] Liu, Yuqi, et al. “Nonerythropoietic Erythropoietin-Derived Peptide Suppresses Adipogenesis, Inflammation, Obesity and Insulin Resistance.” Scientific Reports, vol. 5, no. 1, 13 Oct. 2015, 10.1038/srep15134.
[iv] Europe PMC. “Europe PMC.” Europepmc.org, 2019, europepmc.org/article/med/28383559.
[v] Watanabe, Masaaki, et al. “A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets.” Transplantation, vol. 100, no. 3, 1 Mar. 2016, pp. 554–562, pubmed.ncbi.nlm.nih.gov/26683514/, 10.1097/TP.0000000000001026.
