BACKGROUND: The need to increase the tolerance of various extreme effects is associated not only with the expansion of human professional activity regions but also with the need to assist victims of natural and man-made disasters. The use of pharmacological agents for individual adverse effects is a well-known method; however, considering the combined effects of several physical or chemical factors, only a few references are found in the literature. AIM: This preclinical study aimed to examine the effectiveness of a new derivative of aminoethanol and intermediates of the Krebs cycle in relation to the isolated and combined effects of hypoxia and temperature (hyperthermia and hypothermia). MATERIALS AND METHODS: The fumaric salt of the amber ether of diethylaminoethanol was synthesized at St. Petersburg State University of Chemistry and Pharmacy, Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was conducted on small laboratory animals. Resistance to hypoxia was assessed by the dynamics of the altitude threshold of animals, tolerance to hyperthermia by survival in a thermal chamber at 40°C, and tolerance to hypothermia by the time of maximum swimming in water at 10–12°C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was induced by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, and thermal exposure was induced by placing the animal in water at 40°C (hyperthermia) or 9–11°C (hypothermia). RESULTS: After a single intragastric administration in a wide range of doses, the test compound stimulated the physical performance of animals and exhibited a protective effect under the isolated effects of hypobaric hypoxia, hyperthermia, and hypothermia. With combined exposure to hemic hypoxia and hyperthermia, the compound was effective at a dose of 250 mg/kg. With combined exposure to hemic hypoxia and hypothermia, efficiency was also noted at lower doses (25 and 50 mg/kg). CONCLUSION: Fumaric salt of dimethylaminoethanol amber ether, a new derivative of dimethylaminoethanol, butenedioic, and trans-butenedioic acids, is promising for further study as a means of increasing the body’s resistance to extreme influences.

Introduction. The naïve Bayes classifier combined with principal component analysis allows to distinguish the effects of antipsychotic agents effectively as well as evaluate their dose-dependency based on their impact on electroencephalogram parameters in rats. Further development of this method requires its validation as an instrument for the screening of new understudied molecules. Valproic acid derivatives appear to be a promising neuropharmacological group as they exhibit not only antiepileptic activity but also mood-stabilizing, antimigraine, neuroprotective and analgesic effects.Aim. This work was carried out to perform the pharmacological screening of a valproic acid aminoester (AVA) that exhibits antidote properties in case of poisoning with anticholinesterase agents.Materials and methods. The experiments were conducted in white outbred rats with chronically implanted electrocorticographic electrodes. AVA was administered at doses of 0,5, 5 and 30 mg/kg. The training set, used as a reference to determine the pharmacological effects of each dose of the investigated substance, included matrixes of effects of 7 drugs: the antiepileptic agent sodium valproate, the D2-dopamine receptor blocker haloperidol, the M-cholinergic receptor blocker tropicamide, the H1-histamine receptor blocker chloropyramine, the acetylcholinesterase inhibitor galantamine, the sedative dexmedetomidine, and the anxiolytic phenazepam.Results and discussion. AVA at the dose of 0,5 mg/kg showed effects similar to those of sodium valproate, while a tenfold dose increase led to the predominance of an atropine-like effect. When administered at the dose of 30 mg/kg, the compound exhibited dexmedetomidine-like action. The central M-anticholinergic effect of AVA was confirmed by an arecoline test in mice, in which the substance at a dose of 88 mg/kg completely abolished the onset of tremor. Dexmedetomidine-like action was cancelled by the administration of atipamezole in equimolar quantities, which may indicate the potential сapability of AVA to activate α2-adrenergic receptors at a high dose. The results of molecular docking suggest that this effect is related specifically to the original aminoester molecule and not to its presumable active metabolites.Сonclusion. The obtained results confirm the effectiveness of the naïve Bayes classifier as an instrument for the prediction of the pharmacological activity of compounds based on their impact on electroencephalogram parameters in rats. Identification of new pharmacological effects of understudied compounds may widen the potential range of their clinical application as well as reveal probable adverse effects.

The dynamics of basic parameters of metabolism and lipid peroxidation in the blood serum of rats was studied during the formation of a state of hyperthermia (exposure to air at a temperature of +40 °C for 60 min). It was found that the albumin/globulin ratio, uric acid, cholesterol, triglycerides, blood electrolytes, as well as the activity of the enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, superoxide dismutase, glutathione peroxidase under short-term heat exposure did not have statistically significant differences from the values in the state of normothermia. The level of lipid hydroperoxides and reduced glutathione changes significantly already during the mobilization phase of thermoregulatory mechanisms. The dynamics of these indicators are stable, which allows these indicators to be correlated with hyperthermia itself.

Research into the consequences of human exposure to heavy metals acquires particular significance in the context of life and working age prolongation. Such consequences can be manifested either in the form of selective damage to any organ, organ system or function, or in the form of a general violation of the functions of a number of systems and organs and the organism as a whole, in the form of “disintegration of functions”. In this work, we set out to study the neuroprotective effect of etomerzol fumarate after a subchronic low-dose administration of mercury acetate to Wistar rats. After an intragastric administration of an aqueous solution of mercury acetate at a dose of 4 mg/kg for 30 days, a violation of the learning process was identified in an active avoidance by swimming test. The use of the test substance at a dose of 12.5 mg/kg for 14 days had a positive effect on the long-term memory of animals, contributing to the preservation and reproduction of mercury information received.

A new derivative of dimethylaminoethanol, butanedioic and trans-butenedioic acids (laboratory code ADK-17) was synthesized at the Department of Organic Chemistry (Professor I.P. Yakovlev is the Head of the Department) of St. Petersburg State Chemical and Pharmaceutical University (SPCPU). This is a promising compound planned for use as an oral dosage form. In this work, we aim to evaluate manifestations of the general and specific toxicity of the new drug. Laboratory animals (white mice, rats, rabbits, guinea pigs) were used as test systems for the preclinical safety study of the new compound. Manifestations of general toxicity (acute and chronic), local irritant action, allergenic properties, immunotoxic action were studied. The reproductive toxicity of the ADK-17 drug when administered intragastrically was studied. The studied drug was found to exhibit low toxicity, cause no changes in the biochemical and morphological parameters of rats and rabbits under the conditions of course use, and have no negative effects on internal organs. When administered intragastrically in maximum doses, the drug causes no irritating effects. The use of the drug did not lead to the development of a local allergic reaction of an immediate type. Carrying out sensitization in the DTH reaction showed the absence of a sensitizing effect. The study of the immunotoxic effect of the ADK-17 drug showed that its prolonged intragastric administration for 30 days at doses of 93 and 930 mg/kg did not lead to a violation of the humoral immune response and a decrease in antibody production. Setting a delayed-type hypersensitivity reaction also confirms that the drug does not affect the development of cellular immunity. The conducted experimental studies of the drug’s reproductive toxicity in rats showed that its repeated intragastric administration at doses of 50 and 250 mg/kg to pregnant females did not have a negative effect on the reproductive system of laboratory animals, embryo- and fetotoxic, as well as teratogenic effects, having no effect on the antenatal and postnatal development of offspring.

Introduction. Despite a significant number of antidotes (atropine, pyridoxine) and anti-seizure drugs in clinical practice (benzodiazepines, barbiturates, valproates, anesthetics), the development of new antidotes for the relief of refractory seizures and recurrence of convulsive syndrome is actual problem. The aim of the work was to study the specific pharmacological activity of a new original derivative of valproic acid in an experiment on models of convulsive syndrome with different mechanisms of action. Material and methods. A comparative study of the effectiveness of the original substance ((1-methylpiperidin-4-yl)-2-propylpentanoate hydrochloride, VAA) was carried out on electroshock, GABA-lytic, catecholamine-dependent seizure models in rats and mice. Results. A significant decrease in seizure activity was revealed in the group with prophylactic administration of VAA in the dose range of 11, 27 and 65 mg/kg in comparison with the control group received only phenylcarbamate. In an intergroup comparison, a low dose (11 mg/kg) more than others had an effect on the latent period of the onset of phenylcarbamate seizures, an average dose (27 mg/kg) reduced the duration of the seizure period, a high dose (65 mg/kg) affected the severity of convulsions, while the integral indicator (convulsive activity) did not differ between the medium and high dose subgroups. There was no significant decrease in seizure activity in models with the use of corazol, camphor, and the model of maximum electric shock. Limitations. Testing of new pharmaceutical substances (study of efficacy and safety) should be carried out on laboratory animals before confirmation of efficacy in humans. The quantity of animals was limited by the need to comply with bioethical principles and sufficient number for statistically significant results and amounted 6 individuals in each group. Conclusion. The release of valproic acid during the metabolism of VAA is slow and its concentration is insufficient to realize the universal anticonvulsant activity of VAA. It is necessary to further study the effect on cognitive functions and neuroprotective properties. Since antidote efficacy superior to atropine has been previously demonstrated, VAA is recommended for development as an antidote for organophosphorus poisoning.

Актуальность. К числу разнообразных кислородзависимых патологических состояний относят, в том числе, интермиттирующие, волнообразно протекающие эпизоды гипоксии, чередующиеся с пребыванием человека в условиях нормоксии. Примером подобных состояний является сонное апноэ. Особенности метаболизма при таких состояниях практически не изучались, что и определяет актуальность исследования. Цель исследования: выявить особенности метаболизма у лабораторных животных, подвергающихся хроническому волнообразному кислородному голоданию, для совершенствования диагностических критериев последствий интермиттирующей гипоксии. Материалы и методы. Длительная волнообразная нормобарическая гипоксия создавалась в мембранном гипоксикаторе БИО-НОВА-2004 (Москва), адаптированном для работы с грызунами. Использовался следующий режим работы гипоксикатора: воздушная газовая смесь с содержанием кислорода 14 %, продолжительность единичного гипоксического цикла — 60 минут, интервал между циклами — 30 минут, число циклов в сутки — 6 (суммарный период умеренной гипоксии — 6 часов в сутки), длительность ежедневного гипоксического воздействия — 24 недели. Лабораторные животные (мыши-самцы линии C57BL/6J) были получены из питомника лабораторных животных «Рапполово» (Ленинградская обл.). Содержание животных осуществлялось в условиях сертифицированного вивария в соответствии с требованиями ГОСТ 33044-2014 от 01.08.2015 г. «Принципы надлежащей лабораторной практики» и приказа МЗ РФ от 01.04.2016 г. № 267 «Об утверждении Правил надлежащей лабораторной практики». Биологический материал для исследования (кровь, ткани) у животных забирали на следующие сутки после прекращения гипоксического воздействия. В сыворотке крови определяли активность печеночных ферментов аланинаминотрансфераза (АЛТ), аспартатаминотрансфераза (АСТ), гамма-глутамилтранспептидаза (ГГТП), уровни общего холестерина, липопротеидов низкой плотности и триглицеридов, концентрацию глюкозы. Кроме того, в сыворотке крови определяли содержание нейтральных и основных карбонильных групп белков, а в эритроцитах — активность супероксиддисмутазы (СОД) и каталазы (КАТ). В ткани печени определяли карбонильные группировки белков, содержание суммарных липидов и гликогена; в скелетных мышцах — гликогена. Статистическая обработка полученных данных осуществлялась с помощью прикладного пакета программ для анализа данных (MS Windows 10) с применением методов корреляционного и дисперсионного анализа. Различия считались достоверными при p < 0,05. Результаты. Наиболее выраженные изменения в биохимических показателях после длительного воздействия волнообразного умеренного кислородного голодания отмечаются в клеточных структурах (печень, скелетные мышцы, эритроциты), в то время как показатели, регистрируемые в плазме крови животных, были устойчивы к прерывистому гипоксическому воздействию. Заключение. Возникающий при хронической волнообразной кислородной недостаточности энергодефицит проявлялся в мобилизации углеводных резервов организма, что сопровождалось снижением гликогена в печени и скелетных мышцах в 4–5 раз и вовлечением липидов в качестве субстратов энергопродукции (снижение липидов в печени на 27 %), переключением потока аминокислот на другие виды обмена (снижение активности ГГТП на 14 %). Возникающий дефицит кислорода закономерно сопровождался снижением активности СОД практически в 1000 раз и каталазы в 4 раза, накоплением недоокисленных продуктов (повышение содержания основных карбонильных группировок в белках крови на 41 %). Relevance. A variety of oxygen-dependent pathological conditions include intermittent, undulating episodes of hypoxia, alternating with a person’s stay in normoxia. An example of such conditions is sleep apnea. The features of metabolism in such conditions have not been practically studied, which determines the relevance of the study. Purpose of the study: to reveal thefeatures of metabolism in laboratory animals subjected to chronic undulating oxygen starvation in order to improve the diagnostic criteria for the consequences of intermittent hypoxia. Materials and methods. Long-term undulating normobaric hypoxia was created in a BIO-NOVA-2004 membrane hypoxicator (Moscow), adapted to work with rodents. The following operating mode ofthe hypoxicator was used — an air gas mixture with an oxygen content of 14 %, the duration of a single hypoxic cycle is 60 minutes, the interval between cycles is 30 minutes, the number of cycles per day is 6 (the total period of moderate hypoxia is 6 hours per day), the duration of daily hypoxic exposure is 24 weeks. Laboratory animals (female mice of the C57BL/6J line) were obtained from the nursery of laboratory animals “Rappolovo” (Leningrad region). The animals were kept in a certified vivarium in accordance with the requirements of GOST 33044-2014 of August 1, 2015 “Principles of Good Laboratory Practice” and Order of the Ministry of Health of the Russian Federation of April 1, 2016 No. 267 “On Approval of the Rules of Good Laboratory Practice”. Biological material for research (blood, tissues) was taken from animals on the next day after the cessation of hypoxic exposure. In the blood serum, the activity of the liver enzymes AlAT, AST, GGTP, the levels of total cholesterol, low-density lipoproteins and triglycerides, and the concentration of glucose were determined. In addition, the content of neutral and basic carbonyl groups of proteins was determined in blood serum, and the activity of SOD and catalase (CAT) in erythrocytes was determined. In the liver tissue, the carbonyl groups of proteins, the content of total lipids and glycogen were determined; in skeletal muscles — glycogen. Statistical processing of the obtained data was carried out using the application package for data analysis (MS Windows 10) using the methods of correlation and dispersion analysis. Differences were considered significant at p < 0.05. Results. The most pronounced changes in biochemical parameters after prolonged exposure to wave-like moderate oxygen starvation are observed in cellular structures (liver, skeletal muscles, erythrocytes), while the parameters recorded in the blood plasma of animals were resistant to intermittent hypoxic exposure. Conclusion. The energy deficiency that occurs during chronic wave-like oxygen deficiency manifests itself in the mobilization of carbohydrate reserves of the body, which was accompanied by a 4–5-fold decrease in glycogen in the liver and skeletal muscles and the involvement of lipids as energy production substrates (a decrease in lipids in the liver by 27 %), switching the flow of amino acids to other types of exchange (decrease in GGTP activity by 14 %). The resulting oxygen deficiency was naturally accompanied by a decrease in the activity of SOD by almost 1000 times and catalase by 4 times, the accumulation of underoxidized products (an increase in the content of basic carbonyl groups in blood proteins by 41 %).

BACKGROUND: One of the key transcriptional regulators that determine the bodys resistance to hypoxia is the hypoxia-inducible factor HIF-1, the study of the role of which in the bodys resistance to extreme influences can justify new directions in medical technologies for its increase. The bodys resistance to hypoxia largely determines the resistance to other critically significant influences (hyperthermia, hypothermia, hyperbaria, ionizing radiation, chemicals, etc.). However, it was not possible to find a quantitative assessment of this effect in the literature studied by us, which served as the basis for this study. AIM: To assess the role of the level of expression of the hypoxia-inducible factor HIF-1 in various tissues of laboratory animals in increasing the resistance of animals to the effects of extreme hyperthermia. MATERIALS AND METHODS: The study was carried out on outbred white laboratory rats obtained from the Rappolovo nursery weighing 180220 g. For the study, preliminary laboratory animals were tested for an individual level of resistance to hyperthermia (40 animals), which made it possible to form experimental groups from highly resistant and low resistant to extreme animal influences. The definition of resistance to hyperthermia was carried out by the rate of increase in rectal temperature in animals during 20-minute air hyperthermia (40C). 4 groups of laboratory animals were formed (2 each with high and low resistance), half of which were exposed to a pronounced adverse effect of hyperthermia. Biological material was taken from all animals (whole blood, plasma, tissues of the heart, liver, kidneys, brain), in which the expression of the HIF-1 and TSPO genes (housekeeping gene) was determined by the Real-Time-PCR method. Statistical processing of the obtained data was carried out using the ANOVA analysis of variance. RESULTS: It has been established that the level of resistance of animals to hyperthermia is largely determined by their genetic characteristics. Even under thermocomfort conditions, the expression of the TSPO housekeeping gene in animals with a high level of resistance to hyperthermia differed with a high degree of reliability from low-resistant animals (in the kidneys, liver, and brain, on average, by 4060%; in the heart, by 25%). The expression values of this gene, determined in whole blood or plasma, make it possible to differentiate groups of animals according to the level of resistance to hyperthermia. A similar relationship between animals with high and low resistance is also observed in tissues obtained immediately after thermal exposure. CONCLUSIONS: The main organ that provides a high level of resistance to both hypoxia and hyperthermia associated with the basic (under thermal comfort conditions) expression of HIF-1 is the brain. The expression of the hypoxia-inducible factor in it is more than 300 times higher than the expression of the housekeeping genes. The second most important organ is the liver, in which HIF-1 expression activity is more than 15 times higher than the expression of housekeeping genes. Under conditions of hyperthermia, low-resistant animals show a compensatory-adaptive reaction associated with the activation of hypoxic defense mechanisms in blood cells, kidneys, and liver, in the absence of such a reaction in the tissues of the heart and brain. Animals highly resistant to hyperthermia were characterized by a significant (30 times) increase in the relative activity of HIF-1 expression mechanisms in blood cells, 2.5 times in liver cells, and a decrease in expression by 25% in the kidneys and almost 2 times in brain tissues. A high level of basal expression of the transcription factor HIF-1 under everyday (thermocomfortable) conditions may be a predictor of a high level of resistance to hyperthermia in a given animal. Probably, to increase the bodys resistance to extreme impacts, it is advisable to use medical technologies that increase the level of HIF-1 expression in everyday (thermocomfortable) conditions in key tissues the brain, liver, and myocardium.

BACKGROUND:One of the key transcriptional regulators that determine the bodys resistance to hypoxia is the hypoxia-inducible factorHIF-1, the study of the role of which in the bodys resistance to extreme influences can justify new directions in medical technologies for its increase. AIM:To evaluate the quantitative contribution of the level of expression of the hypoxia-inducible factorHIF-1in various tissues of laboratory animals to the increase in the resistance of animals to the effects of hypoxic hypoxia. MATERIALS AND METHODS:The study was carried out on outbred white laboratory rats obtained from the Rappolovo nursery weighing 180220 g. To conduct the study, animals were previously tested for an individual level of resistance to hypoxia, which made it possible to form experimental groups from highly resistant and low resistant animals. Biological material was taken from all animals (whole blood, plasma, tissues of the heart, liver, kidneys, brain), in which the expression of theHIF-1andTSPOgenes (housekeeping gene) was determined by the Real-Time-PCR method. Total RNA was isolated from the test material by affinity sorption,synthesis of the first strand of cDNA, amplification, followed by determination of the expression level of theHIF-1gene in rats was carried out according to the instructions and the manufacturers protocol by PCR with detection of the accumulation of reaction products in real time (Real-Time PCR) using a CFX-96 detecting amplifier (Bio-Rad, USA) and specific primers and probes for theHIF-1gene in rats (DNK-Sintez, Russia). Statistical processing of the obtained data was carried out using the ANOVA analysis of variance. RESULTS:It has been established that the level of resistance of animals to hypoxia is largely determined by their genetic characteristics. Even under normoxic conditions, the expression of theTSPOhousekeeping gene in animals with a high level of resistance to hypoxia differed with a high degree of reliability from low-resistance animals (in the kidneys, liver, and brain, on average, by 4060%; in the heart, by 25%). The values of the expression of this gene, determined in whole blood or plasma, make it possible to differentiate groups of animals according to the level of resistance to hypoxia. A similar ratio between animals with high and low resistance is also observed in tissues obtained immediately after hypoxic exposure. An analysis of the reaction of the genomic regulation system to extreme exposure showed that it increased the expression of the TSPO gene by 1.62 times equally in all tissues, regardless of the level of animal resistance. For theHIF-1gene, similar patterns were found, but the severity of their manifestations is more and significant. CONCLUSIONS:The main organ that provides a high level of resistance to hypoxia associated with the basic (under normoxic conditions) expression ofHIF-1is the brain. The expression of the hypoxia-inducible factor in it is more than 300 times higher than the expression of the housekeeping genes. The second most important organ is the liver, in whichHIF-1expression activity is more than 15 times higher than the expression of housekeeping genes. Under conditions of moderate hypoxia, a compensatory-adaptive reaction is noted, associated with the activation of hypoxic defense mechanisms in blood and liver cells, and in low-resistant animals, also in the brain tissue. In the myocardium, such a compensatory-adaptive reaction is activated only in the group of highly resistant animals. A high level of basal expression of theHIF-1transcription factor under daily (normoxic) conditions may be a predictor of a high level of resistance to hypoxia in a given animal.

BACKGROUND: Despite the abundance of research in the field of high-altitude physiology and medicine, the problem of resistance to moderate hypoxia has not been practically studied. This is partly due to methodological difficulties: the studies were conducted on healthy people and climbers who tolerated the effects of moderate hypoxia well. Such studies have become necessary in connection with the development of hypoxic therapy. AIM: To search for indicators of the functional state of a person that are highly sensitive to the effects of moderate hypobaric hypoxia. MATERIAL AND METHODS: The examined group consisted of 65 practically healthy men aged 1925 years who were selected for work in high mountains. The main indicators characterizing the state of the central nervous system, cardiovascular and respiratory systems were studied in a state of relative rest and when performing a dosed two-stage bicycle ergometric test, in normoxia conditions (altitude 0) and during a pressure chamber rise in the TABAY climate complex (Japan) to altitudes of 3500 and 4500 m Statistically analyzed were the characteristics of the dynamics of indicators during the transition from normoxia to states of moderate hypoxia, correlations between indicators, their sensitivity to hypoxic effects, the significance of reactivity to hypoxic effects and mobilization of the bodys functional reserves in resistance to hypoxia. RESULTS: It has been shown that the key pathophysiological markers of reduced body resistance to moderate hypoxic exposure are a rapid decrease in the level of peripheral blood saturation, high reactivity of the cardiovascular and respiratory systems to hypoxic exposure, as well as excessive mobilization of the bodys functional reserves in response to additional physical activity. CONCLUSION: The presented materials confirm that the functional state of a healthy person under conditions of moderate hypoxia at rest is determined by the level of saturation of his peripheral blood. Maintaining saturation at a higher level ensures the maintenance of an optimal level of functional state, physical and operator performance, a lower degree of stress on the respiratory and cardiovascular systems.

A comparative evaluation of the effectiveness of dry alcoholic extracts of Dioscorea from pharmacopoeial raw materials and cell cultures was carried out on a model of combined exposure to hypoxic and temperature factors and swimming of laboratory animals (mice) with a load of 5% of body weight. Dioscorea preparations had a pronounced thermoprotective effect and increased physical performance; however, the aftereffect was confirmed only for the cell culture extract.

В статье рассматриваются вопросы взаимодействия хронического низкодозового химического воздействия, характерного для ситуаций экологического загрязнения, и электромагнитных излучений рентгеновского диапазона, кратковременное воздействие которых на организм человека может произойти в нештатных ситуациях профессиональной деятельности. Представлены литературные данные о патогенетических механизмах, которые могут приводить к развитию синдрома взаимного отягощения при комбинированном воздействии химического и физического факторов. Обоснованы направления профилактических и саногенетических воздействий, обеспечивающих сохранение уровня здоровья работников в экологически неблагоприятных условиях. We consider the interaction of chronic low-dose chemical exposure characteristic of situations of environmental pollution and electromagnetic radiation of the X-ray range, the shortterm effects of which on the human body may occur in contingency situations related to professional activity. The literature data on pathogenetic mechanisms that can lead to the development of mutual aggravation syndrome under the combined influence of chemical and physical factors are presented. The directions of preventive and sanogenetic impact to ensure workers' health protection under environmentally unfavorable conditions are substantiated.

The effect of succinic salt of diethylethanolamine fumaric ester on the cognitive abilities of male CBA mice and outbred male rats was studied. It was found that the test substance at doses of 10 and 75 mg/kg in the “Extrapolation escape task” test has a positive effect on the short-term and long-term memory of animals, contributing to the preservation and reproduction of the information received. In the “T-maze” test, the succinic salt of diethylethanolamine fumaric ester in both doses was superior, and in the “Extrapolation escape task” test, it had a comparable effect with the reference drug piracetam (dose 900 mg/kg).

Exogenous RNAs alter interspecifically the transmission of signals in organisms by regulating the expression of their genes. This process leads to phenotypic cellular changes, thus representing a possible new tactic for the treatment of various diseases. Exogenous RNAs are a promising approach to the creation of a fundamentally new class of drugs or biologically active additives (for plant exogenous RNAs) with a promising pharmacological activity and minimal side effects.

Введение. Статья посвящена решению задачи количественной оценки взаимодействия двух неблагоприятных факторов - гипоксического и температурного, при их сочетанном действии на организм лабораторных животных. Исследовали эффекты нормобарической и гемической гипоксии, воздействия высоких и низких температур. цель работы - количественная оценка взаимодействия гипоксии и температурных факторов при их сочетанном действии на организм лабораторных животных. методика. Состояние нормобарической гипоксии моделировали с использованием мембранного гипоксикатора. Установка обеспечивала плавную регулировку концентрации кислорода от 2 до 10% в гипоксической газовой смеси. Гипертермию моделировали путем термостатического поддержания температуры воздуха +40 °С и влажности 30-60%. Гипотермия формировалась в условиях воздушного охлаждения (в холодовой камере при температуре воздуха 5±1 °С и влажности 75-80%). Для оценки функционального состояния проводили тестирование физической работоспособности методом вынужденного плавания с грузом 5% от массы тела в воде различной температуры. Оценка взаимодействия факторов проводилась методом двухфакторного дисперсионного анализа с тремя уровнями выраженности каждого фактора. результаты. Установлено, что гипоксический и тепловой фактор оказывают влияние независимо друг от друга, при превалировании воздействия гипоксии. Взаимодействие между факторами cинергидное умеренное по выраженности, протекает по типу дополняющего эффекта, и может служить основой развития синдрома взаимного отягощения. Воздушная гипотермия слабо влияет на переносимость гипоксического воздействия, влияние иммерсионной гипотермии проявляется более существенно. Заключение. Критическое ухудшение функционального состояния при действии гипоксии и экстремальных температурсопряжено с активацией гипоталамо-гипофизарно-надпочечниковой системы, интенсификацией катаболизма белков, жиров и углеводов, развитием вторичной тканевой гипоксии и формированием митохондриальных дисфункций. Наиболее вероятным механизмом развития синдрома взаимного отягощения при сочетанном воздействии гипоксии и гипертермии является нарушение генерации АТФ в процессе фосфорилирующего митохондриального окисления, который является общим звеном патогенеза различных экстремальных состояний. Introduction. The article focuses on quantitative assessment of the interaction of two unfavorable factors, hypoxia and temperature, during their combined effect on the body of laboratory animals. The effects of normobaric and hemic hypoxia and of high and low temperatures were studied. the aim of the study was to quantify the interaction between hypoxia and temperature factors during their combined effect on the body of laboratory animals.methods. Normobaric hypoxia was produced in a membrane hypoxicator. The oxygen concentration in the hypoxic gas mixture was smoothly adjustable from 2 to 10%. Hyperthermia was modeled by thermostatic maintenance of the air temperature at +40°C and the humidity at 30-60%. Hypothermia was produced in a cold chamber at the air temperature of 5±1°C and the air humidity of 75-80%. Physical performance was tested using forced swimming with a load of 5% of body weight at various water temperatures. The interaction of the factors was assessed by a two-factor analysis of variance for three levels of severity of each factor. results. The hypoxic and thermal factors exerted independent effects, with hypoxia effects prevailing. The factor interaction was synergistic, moderately severe, complementary, and could underlie the mutual aggravation syndrome. Air hypothermia had a slight effect on the tolerance to hypoxic exposure; the effect of immersion hypothermia was more pronounced.conclusion. The critical impairment of the functional state under the action of hypoxia and extreme temperature is associated with the activation of the hypothalamic-pituitary-adrenal system, intensification of protein, lipid and carbohydrate catabolism, development of secondary tissue hypoxia, and the formation of mitochondrial dysfunction. The most likely mechanism for the development of mutual aggravation syndrome under the combined action of hypoxia and hyperthermia is impairment of ATP generation in the process of phosphorylating mitochondrial oxidation, which is a common stage in the pathogenesis of various extreme conditions.

Functional tension of the immune system was considered as depending on the level of physical activity in young people. The subjects were 77 healthy men aged 18–20 years, who were junior students of Yaroslavl universities. The subjects were grouped by physical activity level. The state of the immune system was judged from the lymphocytes phenotype, serum immunoglobulin levels, phagocytic indicators, oxygen-dependent metabolism of neutrophils, and plasma levels of lactoferrin and ferritin. The tension level of specific humoral immunity was inferred from the titers of antibodies to a wide group of bacterial pathogens. The overall tension level of the immune system in subject groups with different levels of physical activity was assessed by the index of conjugation of paired correlation coefficients of immunity indicators. The significance of the controlled factors was assessed by one-way ANOVA in terms of the coefficient of determination; the reliability of the dispersion model was assessed by Fisher’s F -test. The significance of differences between the groups was evaluated by the nonparametric Wilcoxon–Mann–Whitney test. The baseline level of physical activity was not found to act as an activating factor for the immune system. Almost all indicators were within reference ranges optimal for healthy people. At the systemic level, the variability of indicators of various immune processes was determined by stochastic processes without compensatory mechanisms being triggered at the cell and humoral levels. The involvement in regular exercise at a moderate level was a factor that caused not only activation of some mechanisms of the immune response, but also tension in coordinated activity of various mechanisms of immunity as a functional system. Phagocytosis-related mechanisms of immunity and ferritin-dependent reactions were more sensitive in this case. In subjects who had a high level of physical activity and had been involved in regular physical activity for a long period of time, processes of body adaptation to the physical activity regime started to form, being accompanied by a partial decrease in the tension of immunity at the systemic level. Particular indicators of the immune system had higher values (compared to the baseline), while not leaving the reference ranges characteristic of healthy people. Along with the activation of humoral immunity, stimulation of functional activity of cell immunity was observed in subjects with a higher level of fitness. Methodologically importantly, the season did not significantly influence the main immunity indicators with the exception of spontaneous and induced chemiluminescence indicators, whose autumn values significantly differed from the annual average.

Background. A typical extreme factor is hypoxia, which significantly affects the ability to perform tasks of professional activity, in particular, physical activity of various intensity. Physical and neuro-emotional stress under conditions of hypoxia can cause the breakdown of compensatory and adaptive mechanisms with the development of extreme and critical conditions.The aim of the study. Quantitative assessment of the effect of hypoxia on the physical performance of laboratory animals at different levels of their natural resistance.Research methods. Modeling of hypoxia was carried out by the methods of pressure chamber rise of laboratory animals and the administration of a methemoglobin former. Resistance to hypoxic hypoxia was assessed by the criterion of the threshold elevation, to hemic hypoxia – by the lifetime. The criterion for the functional state of laboratory animals was their ability to perform physical activity, which was created by treadmill run or swimming with a load.Results of the study. An altitude of 3500 m causes a decrease in the physical performance of male rats by a third of normoxia level; an altitude of 5000 m – decrease by two times; an altitude of 6500 m – decrease by four times, and at an altitude of 8000 m makes running physical activity by rats impossible. A mild degree of hemic hypoxia causes a decrease in swimming time by almost 2 times, which corresponds to the effect of an altitude of 5000 m on the working capacity; and a moderate degree of hemic hypoxia causes a decrease in swimming time by more than 3 times, which approximately corresponds to the effect of an altitude of 6000 m. The level of resistance to hypoxia has a moderate effect on physical performance, and the factor of a low level of physical performance has almost no effect on the resistance to hypoxia (28 % and 7 % of the trait variability respectively). In animals with an initially low level of resistance to hypoxia, there is also a decrease in working capacity by an average of 20 %.Conclusion. Hemic hypoxia is an adequate model in studies with a complex effect of various extreme factors. Simulation of mild hypoxia caused by the administration of 30 mg/kg of sodium nitrite is an optimal method.