Introduction. The drugs affecting a mitochondrial dysfunction, oxidative stresses, apoptosis and inflammation of the vascular wall, have a high potential for the prevention and treatment of atherosclerotic lesions. In this regard, the use of EPOR/CD131 heteroreceptor agonists which have a similar spectrum of pharmacological effects, is one of the promising strategies in the treatment of cardiovascular diseases.Materials and Methods. The study was carried out on 68 C57Bl/6J male mice. Atherosclerosis was simulated in transgenic animals with an endotheliospecific knockdown of the Polg gene by simulating a balloon injury and keeping on a Western diet. Then, the studied drugs were injected once every 3 days at the dose of 20 μg/kg for 27 days. On the 28-th day, the animals were euthanized and the area of atherosclerotic plaques was assessed. The gene expression associated with the processes of inflammation, antioxidant protection, apoptosis, and angiogenesis was also determined in the aortic tissues. In addition, the endothelium protective effect of peptides on primary cultures of endothelial cells of wild and transgenic Polg-D257A mice was studied.Results. No statistically significant effect of drugs on the area of lipid infiltration have been found. However, the studied peptides have significantly reduced the expression of proinflammatory genes (iNos, Icam1, Vcam1, Sele, Il6, Tnfa), the genes associated with angiogenesis (Vegfa, Kdr, and Hif1a), the expression of proapoptic factors; they decreased the Bax/Bcl-2 ratio by more than 1.5 times. In addition, when supplemented with H2 O2  in vitro, peptides dose-dependently increased endothelial cell survival.Conclusion. The erythropoietin-based peptides can be used to improve the functional state of the vascular wall against the background of atherosclerotic lesions and have a depressing effect on pathobiological processes associated with a mitochondrial dysfunction. In addition, the studied peptides have a significant endothelial protective effect in the induction of oxidative stress in vitro.

The aim of the study was to test whether P-αB can be positioned as a preventing and treating agent for cardiovascular diseases.Materials and methods. The study was performed on sexually mature male Wistar rats. Endothelial dysfunction was modulated by a 7-days intraperitoneal administration of L-NAME at the dose of 2.5 mg/100 g. P-αB, or erythropoietin (EPO), was used for therapy at the dose of 2.5 µg/100 g × 3 times for 7 days, the total dose was 7.5 µg/100 g. The function of endothelium was estimated by an endothelium-dependent and endothelium-independent vasodilation. In addition, a histological assessment of the abdominal aortic wall state and the analysis of eNos, Tnf and Il-1β genes expression were performed. To estimate prothrombotic properties, P-αB and EPO were administered, at the doses of 2.5 and 5 µg/100 g (3 times a day for 7 days, the total doses were 7.5 µg/100 g and 15 µg/100 g, respectively) and on the 8th day, the time of ferric (III) chloride-induced carotid artery thrombosis was estimated.Results. Theresults of the functional tests for endothelium-dependent and endothelium-independent vasodilatation, as well as the histological picture of the aorta have evidenced that P-αB and EPO do not affect L-NAME-induced hypertension but improve the endothelium function. At the same time, P-αB shows a significantly higher endothelial-protective activity, reducing the coefficient of endothelial dysfunction from 5.1±0.15 to 2.72±0.12. In addition, P-αB has significantly increased the expression of eNos and reduced the expression level of Tnf and Il-1β mRNA genes. Carrying out Ferric (III) chloride-induced carotid artery thrombosis has revealed that P-αB (5 µg/100 g × 3 times a day for 7 days, total dose was 15 µg/100 g) has a lower but statistically significant prothrombotic activity than EPO.Conclusion. P-αB can be positioned as an atheroprotector because of its ability to prevent the death of endothelial cells, as well as to reduce remodeling and proinflammatory activation of the vascular wall. However, the prothrombotic properties of P-αB limit its use as a preventing and treating agent for atherosclerosis-associated diseases.

Карбамилированный дарбэпоэтин является перспективным фармакологическим агентом с универсальной цитопротекторной активностью. Его особенностью является отсутствие стимулирующего действия на эритропоэз, которое достигается за счет избирательного взаимодействия с низкоаффинными к эритропоэтину эритропоэтиновыми рецепторами. Для оценки острой токсичности препарат был введен белым лабораторным мышам, а также белым лабораторным крысам подкожно (от 1000 до 5000 мкг/кг) и внутривенно (от 500 до 2500 мкг/кг). Исследовались все критерии в соответствии с действующими рекомендациями, дополнительно анализировались морфологическая картина внутренних органов, активность. При цитологическом исследовании мазка костного мозга в соотношении нормобластов, пронормобластов, моноцитов, сегментоядерных эозинофилов, эозинофильных миелоцитов, сегментоядерных нейтрофилов, палочкоядерных нейтрофилов и нейтрофильных миелоцитов отличий в сравнении с группой, получавшей плацебо, не выявлено. Активность животных, получавших препарат, не имела достоверных отличий от группы, получавшей плацебо. Отсутствие летальности и каких-либо фенотипических изменений (в том числе со стороны красного кровяного ростка) у обоих видов животных позволяет говорить о том, что препарат «карбамилированный дарбэпоэтин» (ООО «Фармапарк», Россия) относится к IV классу малотоксичных лекарственных веществ. Ключевые слова: эритропоэтин, карбамилированный дарбэпоэтин, крысы, гипоксия, острая токсичность Carbamylated darbepoetin is a promising pharmacological agent with universal cytoprotective activity. Its feature is the lack of a stimulating effect on erythropoiesis, which is achieved through selective interaction with low-affinity erythropoietin receptors. To assess the acute toxicity, the drug was administered to white laboratory mice, as well as white laboratory rats subcutaneously (from 1000 to 5000 μg / kg) and intravenously (500 to 2500 μg / kg). All the criteria were investigated, in accordance with the current recommendations, the morphological picture of internal organs and activity were additionally studied. In cytological examination of the bone marrow smear in the ratio of normoblasts, Pronomoblasts, monocytes, segmented nuclear eosinophils, eosinophilic myelocytes, segmented neutrophils, stab neutrophils and neutrophilic myelocytes, there were no differences in comparison with the placebo group. Activity of animals receiving the drug did not have significant differences from the group receiving placebo. The absence of lethality and any phenotypic changes (including from the red blood sprout) in both species of animals makes it possible to judge that the drug carbamylated darbepoetin (Pharmapark, Russia) belongs to the low-toxic drugs (IV class).Известно, что ишемия является одной из наиболее распространенных причин гибели и повреждения клеток. С этим связано наличие консервативных механизмов регуляции кислородного гомеостаза и гомеокинеза. Одна их этих систем, связанная с каскадом гипоксией-индуцируемого фактора, приводит к синтезу эритропоэтина (EPO), предста...

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Activation of the cerebral erythropoietin system can be a promising strategy for the management of various neurodegenerative and neuropsychiatric diseases as it triggers neuroprotective mechanisms and improves cognitive functions. Lack of information about the possible neurotrophic effect of erythropoietin reduces the possibility of using the brain receptor for erythropoietin as a therapeutic target in neurodegenerative diseases associated with hypoxia and inflammation.The investigation aims to study the influence of the erythropoietin receptor agonist -carbamylated darbepoetin (CdEpo) -on the morphofunctional features of neuron-glia networks of primary hippocampal cultures in mice under normoxia.Materials and Methods. Primary hippocampal cell cultures dissociated from embryos (E18) of C57BL/6 mice were used to study the influence of erythropoietin receptor stimulation on the functional activity of hippocampal neuron-glia networks. The experiments were carried out on days 18-23 of culture development in vitro. CdEpo (100 ng/ml) action duration was 24 h. Functional changes were assessed based on the electrical and metabolic activity of cultured cells using patch-clamp techniques, multielectrode registration of bioelectric activity in neural networks and calcium imaging, respectively. The morphological features of primary hippocampal cell cultures were studied using transmission electron microscopy.Results. Treatment of primary hippocampal cell cultures with CdEpo during 24 h did not affect the frequency of spontaneous single action potentials, spontaneous burst activity of cells, the patterns of neuron action potentials (the amplitude of depolarization phase, threshold potential, the amplitude of hyperpolarization phase), membrane capacity. It did not affect the bioelectric parameters of neural network activity (the number of spikes in a network burst, network burst duration, and inter-burst interval), calcium activity of neurons and glial cells determined by the duration and frequency parameters of spontaneous calcium oscillations. At the ultrastructural level, the number of mature asymmetric synaptic contacts remained unchanged under the influence of CdEpo, but there was a morphogenesis of the internal structure of dendritic spines: the number of spines with endoplasmic reticulum and/or the spine apparatus inside increased, which was a unique phenomenon for a model of primary hippocampal culture. Conclusion.There was revealed no neurotropic effect of CdEpo on the model of primary hippocampal culture as reflected by bioelectric activity parameters of single neurons, neuronal networks, and astrocytic network activity evident in the parameters of intracellular calcium concentration changes (calcium oscillations) under normoxia conditions. However, CdEpo causes changes in the internal structure of dendritic spines in some neurons with the spine apparatus appearing in them. The absence of CdEpo effect on the functions of intact neurons and glia indicates the relative safety of using this molecule for therapeutic purp...