This study investigates the therapeutic potential of a new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner’s chronic unpredictable mild stress model of male Wistar rats was used as a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group with saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light–dark box, were used to assess the animals’ conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to the intact animals. These results suggest that Compound I has reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

Ischemic stroke triggers a whole cascade of pathological changes in the brain, one of which is postischemic inflammation. Since in such cases thrombolytic therapy is often not possible, methods that modulate inflammation and affect microglia become particularly interesting. We synthesized 3-(2-oxo-4-phenylpyrrolidin-1-yl)propane-1-sulfonate calcium(II) (Compound 4) and studied its anti-inflammatory activity in in vitro and in vivo models of inflammation and ischemia. Macrophage cell line RAW 264.7 was treated with lipopolysaccharides (LPS) and Compound 4 at various dosages to study the cytokine profile using real-time PCR and cytometric bead array (CBA). Stroke in rats was simulated by the middle cerebral artery occlusion method (MCAO). Several tests were performed to characterize the neurological deficit and locomotor activity of the rats, and afterwards, postmortem, the number of astrocytes was counted using immunohistochemistry. Compound 4 in in vitro tests dose-dependently reduced the expression of interleukin-1β (IL1β), and inducible nitric oxide synthase (iNOS) genes in cell culture and increased the concentration of cytokines: interleukin-2, 4, 6 (IL-2, IL-4, and IL-6). In vivo Compound 4 increased the orienting-exploratory behavior, and reduced neurological and motor deficit. The number of astrocytes that promote and support inflammation was lower in the group treated with Compound 4. The stroke volume measured by magnetic resonance imaging (MRI) showed no difference. We have shown that Compound 4 demonstrates anti-inflammatory activity by increasing the synthesis of anti-inflammatory and reducing pro-inflammatory cytokines, and positively affects the neurological deficit in rats. Thus, Compound 4 has a high therapeutic potential in the management of patients after a stroke and requires further study of its neuroprotective properties.

The increase in the incidence of Parkinson's disease, due to the aging population, is an acute medical and social problem. For a deeper understanding of the pathogenesis of the disease and ways to pre-vent it or pharmacological correction, numerous preclinical studies in animals are needed. The re-view presents the classification of modern models of Parkinson's disease in laboratory animals, the prevalence of use and their pathophysiological mechanisms. Rodents, non-human primates, and some non-mammals are used to model of Parkinson's disease; models can be neurotoxic or genetic in origin. Conclusions were drawn about the translational potential of each model, the possibility of using it for studying pathogenesis or therapy, as well as the complexity of application for researchers.

Introduction: Currently, various mechanisms of the development of depression are known. At the beginning of the 21st century, a new era began in the study of the pathogenesis of this disease. It has been shown that the development of a depressive state is closely associated with neuroinflammation. As a result, it became necessary to develop methods for modeling depression, which will cause inflammation in a strictly defined area of the brain. Purpose of the work: Creation of a model of the depressive state in rats by stereotaxic injection of LPS into the hippocampus. Materials and Methods: Ten female Wistar rats were randomly divided into a control group (n = 3), an LPS-treated group (n = 4), and a sham-operated group (n = 3). LPS was administered at a dose of 30 μg / animal in a volume of 3 μL over 30 min, according to the following stereotaxic coordinates: AP: -3, ML: 2, DV: 3. Depression was assessed in psychopharmacological tests: hole-board test, open field, elevated plus maze, dark-light chamber, Porsolt forced swimming test, sucrose test. The formation of conditioned reflexes of passive avoidance was studied. To assess the localization of the injection, an MRI scan was performed on the 7th day. The result of LPS injection was analyzed on histological preparations. Results: During testing of animals in the setting of a dark-light chamber and an elevated plus maze, it was found that the control and sham-operated groups did not have statistically significant differences. At the same time, the time spent by the rats in the light compartments increased in the experimental group. In the Porsolt forced swimming test, there are statistically significant differences in the time of immobilization of animals. Also, in the rats of the experimental group, the latent period of the onset of reversible actions increased. The study of the formation of a conditioned passive avoidance reflex can be considered not indicative, since two rats from the experimental group and one rat from the group of sham-operated animals did not enter the dark compartment of the installation and did not receive training. In the test for anhedonia, the rats of the experimental group showed a decrease in the consumption of sucrose as compared with the animals of the comparison groups. On histological preparations of the brain at the injection site, the formation of a glial-macrophage "shaft" (hematoxylin-eosin staining) is observed. When analyzing the MRI images, it was proved that the injection was made precisely in the hippocampus of rats. Conclusion: Based on the results of the work, it can be concluded that this method of modeling depression is applicable in fundamental research, since the introduction of lipopolysaccharide into the hippocampus causes neuroinflammation in rats, and as a result, a depression state, and can be used to study the antidepressant activity of new drugs. This work was carried out with the financial support of the Russian Science Foundation grant No. 21-73-20250.

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.

BACKGROUND: In 2021, the Uppsala Monitoring Center of the World Health Organization included 52 vaccines for coronavirus disease-2019 (COVID-19) prevention in the international database, VigiBase, and almost immediately, this group of medicines (drugs) took the lead in the increased rate of reported adverse reactions (ARs). AIM: This study aimed to review the case reports of ARs from COVID-19 vaccines in the VigiBase database. MATERIALS AND METHODS: Statistical analysis of cases that describe ARs in the international pharmacovigilance VigiBase database was performed. RESULTS: On May 12, 2021, the VigiBase database included 26,099,906 reports that describe AR cases on drugs, including 585,744 reports of AR on vaccines for COVID-19 prevention. Serious ARs after immunization with these vaccines were registered in 31.5% of reports, including 0.9% fatal and 1.3% life-threatening. Headache (37.1% of reports), pyrexia (31.1%), chills (23.2%), and fatigue (22.7%) were most frequently recorded. CONCLUSIONS: More data are required to confirm the association between the COVID-19 vaccines and the increased risk of ARs following their use.

This review presents data on the etiology, epidemiology, and pathogenesis of Parkinsons disease from National Center for Biotechnology Information (NCBI), eLibrary, CyberLeninka, and from monographs and textbooks. The prevalence, classification, genetic variability, main pathogenetic links, and potential disease development mechanisms are described. Both classic Parkinsons disease and variable manifestations of parkinsonism are considered. The factors that contribute to disease progression and inhibit its development are described. The main hypotheses of the pathogenetic mechanisms of Parkinsons disease are presented. These are protein misfolding, mitochondrial dysfunction, impaired protein purification systems, neuroinflammation, and pathology of the gut-brain axis.

This review presents information on cases of antibiotic failure (insufficient effect) in the global population over the past three years. We analyzed scientific papers, clinical trial data, and the WHO Program for International Drug Monitoring (VigiBase) data from 2018 to 2020. The values of global success and safety rates of antibacterial drugs for medical use are presented. The findings may be of practical interest to physicians, researchers, developers, and healthcare regulators.

Introduction: More than 4.4% of the world's population suffers from depression, which dramatically reduces both quality and life expectancy. For an accurate understanding of the links of pathogenesis and the possibility of correcting the depressive state, translational studies are widely used - in laboratory rodents. According to the modern concept of the inflammatory genesis of depression, the creation of animal models with nonspecific inflammation on the territory of the central nervous system is an urgent task. Purpose of the work: creation of a model of the depressive state in rats by injecting LPS into the third ventricle of the brain. Materials and methods: the study was carried out on female rats Wistar 280-300g. (n = 10), divided into 3 groups: 1 - with the introduction of LPS (n = 4), 2 - sham-operated (n = 3) and 3 - intact (n = 3). LPS was administered at a dose of 50 μg / animal in at volume of 4 μl in 15 minutes, according to the following stereotaxic coordinates: AP-0.8 ML-1.5 DV-3.5. Depression was assessed using the sucrose test and the behavior of animals in the open field tests, the elevated plus maze, the dark-light chamber, and the Porsolt test. Confirmation of the correct administration was carried out using MRI scanning (7 days) and postmortem on histological sections. Results: Animals treated with LPS showed a decrease in sucrose consumption, both compared to the sham-operated group and compared to the intact group. In behavioral tests, there was a decrease in locomotor activity in rats with the influence of LPS, but the differences between the group of sham-operated rats were insignificant. The experimental group had a sharp increase in the time of immobility in the Parsolt test (89.6 s VS 32.6 s VS 22.2 s) for the first, second and third groups, respectively. In the behavior of animals in the burrow chamber and in the open field, the presence of a neurological deficit in the experimental group was noted, consisting in a violation of gait in three out of four rats, in other groups this effect was not observed. When analyzing MRI images, the trace from the needle is traced exactly to the third ventricle. On a histological section in rats with neurological deficit, a demyelination area is visible (Fig. 1). Conclusion: The introduction of LPS into the cavity of the third ventricle causes depressive-like behavior in rats, a decrease in locomotor activity, but causes manifestations of neurological deficit as a result of local demyelination of the nervous tissue. The work was carried out within the framework of the state assignment of the Federal State Budgetary Educational Institution of Higher Education named after V.I. N.I. Pirogov for 2021–2023, state no. registration research work AAAA-A18-118051590108-1

Dyslipidemia makes a substantial contribution to the mortality as one of the leading pathogenetic factors for cardiovascular diseases. The nature and degree of the effect on the blood lipid spectrum may vary in the lipid-lowering drugs from different groups. Recently, a new class of PCSK9 inhibitors has been developed, which activity is associated with a protein involved in the low-density lipoprotein receptor control. In clinical practice, this group is represented by monoclonal antibody drugs evolocumab and alirocumab. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are promising drugs to be used in the combination lipid-lowering therapy, which, given the results of clinical trials, can be recommended at this point on a third-priority basis after statins and ezetimibe. However, it is vital to indicate that these drugs have a sufficient safety profile, which makes it possible to prescribe these drugs in a triple combination adding it to the two first-line drugs regimen which patients had been given before. It is obvious that further study of PCSK9 will expand the range of their use for the treatment of familial hypercholesterolemia up to indications in cases where statins are limited and a more pronounced lipid-lowering effect is required to achieve target cholesterol levels.

Here we examined distribution of Na/K-ATPhase α-subunit in rat cerebral structures, which activity changes in Parkinson-like syndrome. The study was aimed at analyzing quantitative change in diverse different isoforms of Na/K-ATPhase α-subunit in model of Parkinson-like syndrome as well as after refining it by using thymus hormone thymulin. The study was performed on 42 sixweek-old Wistar rats males by dividing animals into 3 groups: 2 experimental and 1 control group. To simulate Parkinson-like syndrome, a solution of 1-methyl 4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) was administered intranasally. 10 days after MPTP inoculation, thymus hormone thymulin was abdominally administered to animals in one experimental group for 5 days. It was demonstrated that level of tissue-specific isoforms of Na/K-ATPhase α-subunit was peaked in hypothalamus, amygdaloid body and striatum, the minimal level was observed in medial prefrontal and prefrontal cortex. It was estimated that in MPTP-stimulated model of Parkinson’s disease, the level of Na/K-ATPhase α1-subunit was significantly higher in striatum, amount of α2-subunits was decreased in the hippocampus, whereas the level of α3-subunit was elevated in the cerebellum compared to control group. Administration of thymus hormone thymulin corrected changes in level of α1, α2 and α3-subunits observed after exposure to neurotoxin.

Arterial hypotension syndrome is inherent in a number of organic and functional diseases. Different causes of hypotension determine the spectrum of medicines used to increase blood pressure. Hypotension can cause fatigue and dizziness, but the necessary exercise programs can be sufficient to normalize the condition without the intervention of drug therapy. In children and adolescents, primary arterial hypotension develops against the background of vegetative-vascular dystonia syndrome with vagotonia-specific clinical symptomatology. It can take an unstable reversible course. The article presents drug-free modalities of the treatment of hypotension and examines medicines that raise blood pressure. Medications of this group are used both in shock states of various genesis and collapses, and in arterial hypotension, allergic reactions, especially accompanied by low blood pressure, and in bronchial asthma. The choice of drugs is determined, first of all, according to the nosological form, the state of basic myocardial functions (contractility, excitability, and automatism), intensity of adverse reactions, presence of concomitant diseases, and functional state of excretion organs.

The study of behavior and cognitive functions is rather difficult to interpret, is time-consuming and has a number of peculiarities both in planning the study and in conducting the tests themselves. For this kind of experiments, Various biomodels are used for such experiments, but this paper we will focus on experiments on the animals most often used in laboratory practice - small laboratory rodents (rats and mice). Most often, there is a need to carry out psychopharmacological studies in order to examine the specific activity of drugs belonging to the group of psychotropic drugs, however, medicine from other pharmacological groups can also have neurotropic activity and expressly influence the behavior and cognitive functions of both animals and humans. The paper highlights the main stages of planning and conducting a study of behavior and cognitive functions, starting with the analysis of power and calculating the sample size, the formation of experimental groups and ending with the features of data interpretation. It also presents the most commonly used psychopharmacological tests, as well as methods for confirming neurological deficits. Thus, it is possible to highlight a number of points enabling the most accurate determination the spectrum of psychotropic action of the studied drugs: The number of animals in groups should be sufficient for statistical analysis and usually ranges from 12 to 14 per group. When forming groups, it is necessary to type the behavior of animals using the Open Field test or its analogue and create groups of animals identical in behavior. When studying the spectrum of psychotropic action, one should not be limited to one or two narrowly targeted tests, but use a whole range of behavioral tests for the most complete picture of the drug's action. When assessing the effect of the drug in some cases, one should not average the results in a group, but use an assessment of the individual change in behavior of each animal.

Разработка методов медикаментозной терапии и реабилитации в разных периодах ишемического поражения головного мозга в настоящее время является актуальной проблемой. Целью исследования было изучить фармакокинетику и антиишемическое действие нового производного 4-фенилпирролидинона-2 на крысах. Для изучения фармакокинетики крысам линии Wistar однократно вводили вещество в дозе 250 мг/кг, затем оценивали его распределение в плазме и коре головного мозга. Установлен период полувыведения (Т1/2), 83,2 мин. Время нахождения вещества в тканях головного мозга составило 24 ч. Для оценки антиишемического действия проводили моделирование инсульта методом эндоваскулярной транзиторной окклюзии средней мозговой артерии, препарат вводили внутривенно в течение 5 дней в двух дозах, 250 и 125 мг/кг. Затем определяли размер очага поражения (с помощью МРТ), степень неврологического дефицита, локомоторную и исследовательскую активность. Исследуемое вещество значимо снижало неврологический дефицит у модельных животных по сравнению с контрольной группой (1,72 vs 4,4; p < 0,05). Влияние на очаг ишемии по МРТ было незначительным, а ориентировочно-исследовательское поведение под воздействием производного 4-фенилпирролидинона-2 значимо активизировалось («норковая камера», горизонтальная активность 12,1 ± 6,8, 22,5 ±10,5; p < 0,05). Полученные данные позволяют сделать вывод, что исследуемое вещество проходит через гематоэнцефалический барьер (ГЭБ), накапливается в коре головного мозга, способствуя коррекции неврологического дефицита и повышая исследовательскую активность у животных в модели ишемического инсульта.

The development of methods of drug therapy and rehabilitation in different periods of ischemic cerebral lesion is currently an urgent problem. Our study was aimed to investigate the pharmacokinetics and anti-ischemic effect of the new 4-phenylpyrrolidone-2 derivative in rats. To study the drug pharmacokinetics, the Wistar rats were once administered with the substance at a dose of 250 mg/kg, then, the substance distribution in blood and cerebral cortex was evaluated. Elimination half-life value was determined, which was 83.2 min. The substance remained in the brain tissue for 24 hours. To assess the anti-ischemic effect, the stroke was modeled by endovascular middle brain artery transition occlusion, and the drug was administered intravenously for 5 days at two doses, 250 and 125 mg/kg. After that the lesion focus volume was evaluated by MRI, as well as the neurological deficit severity, locomotor and explorative behavior. The studied drug significantly decreased the neurological deficit in model animals compared to control group (1.72 vs 4.4, p < 0.05). According to the MRI data, the effect on the ischemic focus was negligible, while the explorative behavior significantly increased under the influence of the 4-phenylpyrrolidone-2 derivative (hole board test, horizontal activity 12.1 ± 6.8, 22.5 ±10.5, p < 0.05). The data obtained allow us to conclude that the studied substance penetrates the blood-brain barrier (BBB), and accumulates in the brain tissue promoting the neurological deficit correction and increasing the explorative behavior in the ischemic stroke model animals.

A comparative study of the effect of the thymus hormone thymulin and thymus peptides (thymosin fraction 5) on the content of monoamines and their metabolites in the frontal cortex, striatum, adjacent nucleus, hypothalamus, hippocampus of the brain of Wistar rats, by high performance liquid chromatography, was performed. The hormone and peptides of the thymus were found to reduce emotional stress during functional impairment ofthe avoidance reaction and improved adaptation under stressful conditions in rats, which indicates the anti-stress effect of thymus hormones. The positive effect of the hormone and peptides of the thymus were manifested in a change in the balance of serotonin and norepinephrine in favor of the former in the hypothalamus and frontal cortex.

Non-steroidal anti-inflammatory drugs (NSAIDs) are included in a pharmacological group of drugs with different chemical structures providing anti-inflammatory, analgesic and antipyretic actions, as well as antiplatelet action to a certain degree. Unfortunately, NSAIDs can cause a wide range of adverse reactions (AR) posing a serious risk to the health and life of patients. Therefore, the rational use of NSAIDs should include methods for effective prevention of drug complications. Many NSAIDs have a pronounced therapeutic effect, simultaneously causing many undesirable effects, so the drug shall be chosen considering the development of predicted side effects and modern algorithms. According to clinical recommendations, risk factors and administration of safer NSAIDs shall be considered as the main prevention method. Besides, it is possible to protect the patient from the upper gastrointestinal tract complications using proton pump inhibitors. It should be noted that there are no effective medication methods for kidney and liver protection to reduce the risk of NSAID-associated complications.

The review article presents a summary of adverse drug reactions (ADR) in children, information about which was received in 1968–2018 in the International database VigiBase (Uppsala monitoring center, UMC). Of the 18.4 million Individual Safety Case Reports (ICSR) received over 50 years by VigiBase, 1.47 million ICSR contain information on the safety of pharmacotherapy in patients under the age of 18, including: 34 510 reports contain information on ADR in children under the age of 27 days, 415 678 — in children aged 28 days to 23 months, 613 676 — aged 2 to 11 years and 405 202 ICSR — in patients aged 12 to 17 years inclusive. During 2018 141 655 ICSR ADR of children in VigiBase was received. The most common reason for submitting reports on adverse effects in children was vaccines, antibiotics, non-steroidal antiinflammatory drugs, analgesics-antipyretics, anti-acne and valproic acid. The most common side effects of drugs in children were the following ADR: hyperthermia, rash, vomiting, nausea, urticaria, diarrhea, itching, headache, erythema at injection site, convulsion. Separate data on 6 age groups about 10 most frequent ADR in children and about 10 medicines which ICSR most often arrived in VigiBase for 50 years and for 2018 are given.

Thymus polypeptides participate in stress-limiting system work. Considering that electropain stimulation is the main stress factor in many behavioral models, it is logical to assume that thymus polypeptides have analgesic activity. The objective of this research is study of opioid and serotoninergic systems role of thymus polypeptides analgesic endpoints implementation. The rats presented with tactivin and thymulin thymus peptides analgesic activity during tail withdrawal test, which is totally blocked by naloxone, and thus is based on opioid system activation. This effect is associated with appeared serotoninergic component of stress-induced analgesia. The possible mechanism of analgesic action and the role of serotoninergic system of thymus peptides were offered based on the results of the research conducted.