Cibinetide, more commonly known as ARA 290 peptide is a peptide agonists of erythropoietin receptors that do not affect erythropoiesis (depression, ara 290 neuropathy, neurite growth, neural culture survival, axonogenesis, short-term memory, CNFD, cardiac function). More about buying ARA 290 Peptide.
ErythropoietinIs a renal glycoprotein hormone, which is synthesized mainly by cells in the renal cortex and, in small amounts, in the liver and brain. The hormone molecule contains 193 amino acid residues with a total mass of 21 kDa. Erythropoietin has a wide range of effects in the body, including vasoconstriction-induced increases in blood pressure, stimulation of angiogenesis (the process of blood vessel formation), and promoting cell survival, which results in reduced cell death in damaged ischemic tissues.
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In addition, some studies have shown its neuroprotective effect in diabetic neuropathy and in patients with chronic renal failure. Erythropoietin participates in the mutually regulated process of maturation of red blood cells (erythrocytes), this process is callederythropoiesis. The content of hemoglobin and erythrocytes in the blood is maintained at a normal stable level, which is optimal for the full delivery of oxygen to the tissues of the body. The level of erythropoietin in the blood is about 10 mU / ml, however, under hypoxic stress, its production can increase 1000 times.
It is known that erythropoietin exerts its effect by binding to the erythropoietin receptor. This activates signaling cascades leading to differentiation, survival, and proliferation of erythrocyte progenitor cells. Negative regulators of cytokine signaling are also expressed. Various erythropoietin agonists, erythropoiesis stimulants, which are used to treat anemia caused by kidney disease, chemotherapy, major surgery, or HIV / AIDS therapy have found application in medicine. It is also known about its use in sports requiring great endurance: boxing, rowing, running, etc.
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In turn, an increased content of red blood cells causes an increase in blood viscosity, their adhesion in the bloodstream and an increase in blood pressure, which can lead to thrombosis, heart attacks and other dangerous diseases. There are erythropoietin agonists with pharmacologically valuable properties that do not affect erythropoiesis. These include Cibinetide (ARA-290) and Epobis.
ARA290 ( Cibinetide ™, Cibinetide, Araim Pharm aceuticals, Inc) is a neuroprotective synthetic derivative of erythropoietin consisting of 11 amino acid residues :
pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser-OH (pyr – pyroglutamic acid residue)
ARA290 is a non-erythropoietic derivative that does not increase the risk of cardiovascular complications, but potentially has cytoprotective properties in the prevention of renal ischemia and reperfusion injury.
In experiments on an animal model– female Dutch Landrace pigs, who underwent unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney, were injected with ARA290 by intravenous injection 0, 2, 4 and 6 hours after reperfusion (restoration of blood flow through the coronary arteries after ischemia) . Saline was used as a reference drug. ARA290 increased glomerular filtration rate over a seven-day follow-up period. In addition, ARA290 tended to decrease the expression of MCP-1 and IL-6 15 minutes after reperfusion. Seven days after reperfusion, ARA290 reduced interstitial fibrosis. This effect on structural damage suggests that ARA 290 peptide with transplantation may positively influence graft survival .
In a study on a renal allograft model in rats, a titanium bridge with a ring post was installed. The kidneys were removed 24 hours after transplantation to: study the protective effect of ARA290 peptides on renal morphology and function; investigate the mechanism of the binding affinity of nuclear factor-κB (NF-κB) with DNA; Observe the effect of ARA290 at a concentration of 1 nmol / ml on macrophage infiltration using immunohistochemistry; and detect the expression of messenger RNA (mRNA) of inflammatory mediators by reverse transcriptase PCR.
In the ARA290 group, renal morphology was significantly improved and there was also a decrease in macrophage infiltration. The binding of NF-κB to DNA in the ARA290 group was markedly lower than in the control groups. Expression of mRNA effectors of NF-κB (monocyte chemotactic protein-1;
In experiments on rats that survived 2 or 20 weeks after injury, the effect of ARA290 at a dose of 10 and 30 μg / kg on the response of microglia (iba-1-IR) and astrocytes (GFAP-IR) was assessed . ARA290 dose-dependently reduced allodynia (pain caused by stimuli that usually does not cause it, and arising as a result of damage) in combination with suppression of the spinal microglia response, which allows conclusions to be drawn about the relationship between ARA290-induced suppression of central inflammation and amelioration of symptoms of neuropathic pain .
ARA290 is also known to prolong health and attenuate age-related deterioration in heart structure and decreased function , as has been shown in brown Norwegian rats . The rats received ARA290 injections twice a week. Body weights were recorded every 2 weeks and echocardiograms before and during double autonomic blockade at 18, 22, 26, 30 and 33 months of life and their health impairment was assessed by assessing changes in heart markers over time. Based on the data obtained, the overall risk of death was predicted. It has been found that the effects of ARA290 on the aging process of the heart may contribute to the observed improvement in health outcomes. .
In phase I and II clinical trials in 2014–2017. in humans (36 healthy volunteers, dose 2 mg), the effect of ARA290 on cognitive and neural processing of emotions was assessed 7 days after administration, as well as the drug’s potential for treating depression . The control group took a placebo. The drug was well tolerated. 14 people took part in multiple drug intake, no serious adverse events were observed, with the exception of a single case of loss of consciousness after administration of 700 μg ARA-290; the subject recovered without medical intervention. The emotional state after a one-time intake of the ARA 290 peptide is comparable to playing computer games (according to the results of the emotional processing test), and a slight improvement in mood was also found.
In 2014-2017 A Phase II clinical study of the effect of ARA-290 on corneal nerve fiber density and neuropathic symptoms in patients with sarcoidosis was carried out. 64 patients were divided into 4 groups. Each group received 1, 4, 8 mg ARA-290 or placebo. The examination was carried out 14 ± 2 days after the start of treatment, 28 ± 2 days at the end of treatment, and 56 days after the start of the study. Patients showed a significant increase in CNFD compared with no change in the placebo group .
Also in 2013–2015. studied the effect of ARA290 on blood glucose and insulin secretion in individuals with prediabetes or type 2 diabetes. The trials were in phase II, but the data on the results of the study were not included in the database of clinical trials . At the same time, the conditions and results of this test are described in . Patients (24 subjects, 63.0 ± 1.5 years) were injected subcutaneously with ARA290 4 mg daily for 28 days, then the volunteers did not take the drug for a month. As a result, during 56 days of follow-up, the patients showed an improvement in the hemoglobin A1c (Hb A1c) and lipid profiles. Neuropathic symptoms improved significantly in the ARA290 group. The average density of nerve fibers in the cornea was significantly reduced compared to the control. These observations showtreating neuropathy in patients with type 2 diabetes . The drug was well tolerated.
In 2016, the FDA assigned the ARA290 peptide, manufactured by Araim Pharmaceuticals, Inc, the status of an orphan drug i.e. a pharmaceutical product developed for the treatment of rare diseases. This fact indicates the importance of this peptide.
Epobis was first synthesized in 2012. This peptide corresponds to the C-terminal region of the AB loop (36NENITVPDTKVNFYAWKR53 amino acid residues 36–53) of human erythropoietin and is its mimetic. The amino acid sequence of the peptide consists of 18 residues:
The Epobis ARA 290 peptide specifically binds to EPOR and induces the growth of neurites from primary neurons in an EPOR expression-dependent manner. In addition, Epobis promoted the survival of hippocampal and cerebellar neural cultures . Epobis has the potential to stimulate neuroregeneration and neuroprotection and, when treated with 1 μM for 24 hours, promoted in vitro survival of rat and puppy hippocampus and cerebellum neural cultures after model cell damage by kainate and KCl deprivation, respectively.
In in vitro studies, Epobis promotes axonogenesis in primary motor neurons and has anti-inflammatory effects, as evidenced by its ability to reduce TNF release from activated macrophages AMJ2-C8 and primary rat microglia. When administered systemically, Epobis (10 mg / kg subcutaneously twice a week, 5 weeks) is found in both plasma and cerebrospinal fluid, demonstrating the ability of the ARA 290 peptide to penetrate the blood-brain barrier.
Systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The ARA 290 peptide has long-term effects on short-term memory defined as an improvement in social memory 3 days after administration. This is confirmed in an experiment on female rats, which were injected with Epobis (10 mg / kg, 1 ml / kg, subcutaneously.),
And after 1 hour the test animals were presented with an unfamiliar young male for 4 minutes. After another 2.5 hours, the same young rat was re-administered, or an unfamiliar young rat was administered. In order to test the long-term effects of the peptide, a repeated social recognition test was performed 73 hours after drug administration. A series of experiments revealed an improvement in the social memory of animals; also confirmed the absence of hematopoietic effect with prolonged use.
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The available data on the biological activity of the peptides Cibinetide (ARA-290) and Epobis indicate their wide potential for use in various fields of medicine, including transplantology, cardiology, the fight against neurodegenerative diseases, gerontology, etc. Their clear advantages in comparison with erythropoietin can be attributed to a wider range of effects on the body and the lack of stimulation of erythropoiesis. It is worth noting that further research could significantly expand the use of the ARA 290 peptide.