Relevance. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive and behavioral disorders. The drugs currently used in clinical practice can slow drug development but are usually associated with lifelong use because of the complexity of pathogenesis. Therefore, to correct AD, a similar approach is needed, which can be CAPAH (2-chloroethoxy-para-N-dimethylaminophenylphosphorylacetohydrazide), a potential drug with a multitarget mechanism of action.Objective. Investigate the effects of CAPAH, memantine, and rivastigmine on the behavior and cognitive functions of rats.Materials and methods. This study identified CAPAH as a potential drug with a multitarget mechanism of action. The comparator drugs were memantine (10 mg/kg) and rivastigmine (2 mg/kg). Animals were divided into 4 groups (control, CAPAH, memantine, rivastigmine), 8 males and 9 females each receiving subcutaneous injections of the respective agents for 30 days. Subsequently, their cognitive functions and behavior were studied on the «Morris Water Maze» (MWM) and «Extrapolation deliverance» (EPI) ("Open Science", Russia) with the help of the "EthovisionXT" program (Noldus, the Netherlands). Statistical processing was performed using one-way ANOVA in the GraphPadPrism 8.0.1 program.Results. In case “MWM” CAPAH increased the swimming time in the platform zone by 1.8 and 1.5 times (p < 0.05) compared with the control in the male and female groups, respectively, exceeding the parameters of the comparison drug. In case "EPI" test, the administration of CAPAH to males reduced the number of jumps by 4.4 times (p < 0.05) and increased the latent period of motor activity by 2.3 times (p < 0.05) compared with the control group, but did not affect these aspects in females.Conclusion. Administration of CAPAH improves cognitive function and memory in healthy male and female rats and reduces anxiety in male rats, whereas it outperforms the effects of memantine and rivastigmine.

Relevance. Drug pollution of the environment is a global environmental problem of our time. Increased consumption of medicines directly affects the level of pollution of various ecosystems, including water resources. The insufficient efficiency of existing methods for treating wastewater from drugs leads to drug pollution of water bodies and requires studying the effect of ultra-low doses of drugs on the human body and animals. A non-steroidal antiinflammatory drug, diclofenac, was detected in surface water samples in Kazan at a concentration of 1×10−9 M.The purpose of this study is to study the presence of specific pharmacological effects of diclofenac detected in water samples in ultra-low doses in experimental models of pathological processes.Methods. The experiment used 21 male white laboratory mice, which were divided into three groups (each with 7 mice). For 4 days, mice were intragastrically injected with distilled water (control group), diclofenac solution 1×10−6 M (experimental group No. 1), diclofenac solution 1×10−9 M (experimental group No. 2). On the fifth day of the experiment, inflammation was induced by injecting carrageenan lambda (1 %, Sigma) subplantarly into the right hind paw in a volume of 0.05 ml. The amount of edema was determined using an IITC Life Science plethysmometer (USA).The results of an experimental study of the specific pharmacological activity of diclofenac showed that diclofenac in ultra-low doses of 0.32×10−3 mg per 100.0 g of weight is able to reduce the severity of acute inflammation caused by subplantar injection of carrageenan and to cause NSAID-associated gastropathy in mice.Conclusion. The obtained data likely indicate a potential risk of adverse effects from drug contamination of the environment with diclofenac, even in ultra-low concentrations.

Introduction. Behavioral methods on laboratory animals are recognized as the main approach in studying the activity of potential psychotropic drugs and allow us to evaluate the main effects of new compounds, increase the possibility of predicting a successful outcome of future clinical trials.Text. This review article analyzes the main modern behavioral models in rodents that are widely used for screening and studying the pharmacological activity of potential psychotropic drugs. The advantages and disadvantages of each test are highlighted and complexes of behavioral methods are demonstrated that most conclusively confirm the reproducibility of the results obtained in clinical trials. The description and evaluation of behavioral methods that characterize the state of anxiety, which are used to screen for new compounds with anxiolytic activity (tests «Open field», «Dark-light chamber», «Elevated plus maze», «Sequence of rays»). The range of tests used to study cognitive functions and memory processes is widely presented (various mazes – T-shaped, U-shaped, radial maze, Barnes maze, E-maze; water mazes – Morris, T-maze) with a description of a comparative analysis and necessary conditions that ensure the reliability of information. An important direction in the field of behavioral pharmacology is the modeling of violations of social behavior and the study of approaches for its correction – the main methods necessary for the study of social behavior are presented in the review by the tests «Three-chamber social test», «Open field» extended test, etc.Conclusion. Behavioral pharmacology dictates the need for close interaction between preclinical and clinical stages of research in the framework of the development of translational medicine and the development of approaches that provide evidence for the reproducibility of the results obtained in clinical trials. It is also necessary to improve existing and develop new behavioral models of mental disorders and to search for new ways to study the mechanisms of formation of behavioral disorders.

Relevance. It is known that the existing drug therapy for cognitive disorders is characterized by low rates of efficacy and safety, as well as symptomatic orientation. Therefore, the search for new drugs in this area is an urgent issue, the solution of which can be phosphorylated derivatives of thiosemicarbazides (PTC), which have a multitarget mechanism of action. Aim. Study of acute toxicity and behavioral effects of PTC in mice. Methods . The objects of study are 2 new compounds of the PTC series: 2-[2-(Diphenylphosphoryl)acetyl]hydrazinecarbothioamide (T7) and 2-[2-(Diphenylphosphoryl) acetyl]-N-phenylhydrazinecarbothioamide (T8). The reference drug is diphenylphosphorylacetic acid hydrazide (phosenazid). After determining the acute toxicity with a single intraperitoneal injection, the effect of PTK on the behavior of mice was studied in the models "Open field" (OP), "Elevated plus maze" (EPM), "Dark-light chamber" (DLC) and "Behavioral despair" (BD). For statistical analysis, the GraphPadPrism 8.0.1 program was used with the calculation of Student's t-test. Results. It has been established that new PTC are less toxic than fosenazid. Behavioral testing showed that i.m. administration of T8 in test "OP" contributed to an increase in exploratory (6 and 12 mg/kg) and motor (12 mg/kg) activity, the development of an anxiolytic effect in the tests "EPM" (12 mg/kg) and "DLC" (6 mg / kg), and in "BD" (12 mg / kg) antidepressant effect. With the intravenous administration of T7, an increase in motor activity in the “OP” (16 mg / kg) was noted. Conclusion . Compounds of a number of PTC are promising for further synthesis and development as potential drugs with a different spectrum of psychotropic activitys.

We report here studies using an experimental model of autism created by prenatal administration of valproic acid to produce a comparative analysis of behavioral disorders in female and male rats, along with indicators of relative levels of expression of the Drd1 dopamine receptor gene in brain structures playing a significant role in disorders of social behavior and the development of anxiety – the prefrontal cortex, amygdala, cerebellum, and hippocampus. The state of anxiety in the valproate model of autism was found to develop only in males, while disorders of social behavior were typical of rats of both sexes, though the nature of these disorders differed in females and males: in the three-chamber social test, males preferred to spend more time in the compartment with a familiar animal, while females preferred to spend significantly less time with a novel, unfamiliar rat, as compared with control animals. Sex-related differences were found in the relative levels of expression of the Drd1 gene in the prefrontal cortex, amygdala, and cerebellum: the relative level of Drd1 expression was greater in the prefrontal cortex and amygdala in females, while males, conversely, showed significantly lower expression in the cerebellum in relation to both males of the control group and females. Analysis of the results obtained here indicates that there is a need to consider changes in the relative levels of Drd1 expression in all study areas simultaneously, evaluating the overall changes in the expression profiles of this gene, which may underlie sex-related differences in both communication disorders and other possible behavioral changes in the valproate model of autism in rats.

Relevance. Alzheimer's disease (AD) is a neurodegenerative disease, the drug therapy of which can only slow the progression of the disease, due to the variety of existing pathogenetic processes. A possible effective approach to the correction of symptoms can be the use of compounds with a complex mechanism of action — phosphorylacetohydrazides, capable of simultaneously acting on different parts of the pathological process, the most effective representative of which is the compound 2-chloroethoxy-para-N-dimethylaminophenyl phosphorylacetohydrazide (CAPAH). Target. To study the possibility of correcting cognitive and behavioral disorders in rats with a stereotaxic model of AD using the CAPAH compound, which affects different parts of the pathological process. Methods . 24 female Wistar rats were used in the work. AD was modeled in rats by stereotaxic bilateral injection of β-amyloid into the hippocampal region in a phosphate buffer solution, then on day 11, CAPACH (10 mg/kg) was administered intraperitoneally for 10 days, after which tests were performed using the ≪Elevated Plus Maze≫, ≪Open Field≫ and ≪Morris Water Maze≫. Statistical processing was carried out in the GraphPad Prism 8.0.1 program using one-way ANOVA analysis. Results . Multiple administration of CAPAH contributed to a decrease in the level of anxiety in the ≪Elevated Plus Maze≫ method, increasing the time spent in open arms by 4.6 times ( p < 0.05) compared to rats without treatment. In the ≪Morris Water Maze≫ and ≪Open Field≫ tests, normalization of memory and motor activity processes was observed, respectively, the platform search time and the number of crossed lines did not differ from those of control animals. Conclusion . CAPAH reduces anxiety and memory processes in rats with a stereotaxic model of Alzheimer's disease caused by the introduction of β-amyloid into the hippocampus.

Aim. To study the indicators of metabolic changes in the blood and brain structures of rats after exposure to hypobaric hypoxia and to determine possible pharmacological approaches to correction these changes. Methods. Hypobaric hypoxia in rats was simulated for 30 minutes in a pressure chamber, simulating an ascent to 8500 m. 3 and 24 hours after hypoxia, the activity of alanine aminotransferase, aspartic aminotransferases, alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase, the content of glucose, total protein, triglycerides, cholesterol, -lipoproteins, iron and uric acid were determined in the blood serum. The level of malondialdehyde in the hippocampus and frontal cortex was examined. The studies of the effect of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide (CAPAH) (1 mg/kg) and Рiracetam (100 mg/kg) after intraperitoneal injection 40 minutes before hypoxia and 1 hour after removing the rats from the pressure chamber were carried out. Statistical analysis was carried out using the GraphPad Prism software version 8.0.1, and the Student's t-test was used to test statistical significance. Results. After 3 hours of hypobaric hypoxia, rats showed hyperenzymemia and dyslipidemia, the activity of almost all studied enzymes in the blood serum of rats was increased, the content of triglycerides was decreased, and the concentration of cholesterol was increased, the content of malondialdehyde in the hippocampus and frontal cortex was increased. In 24 hours after hypoxia, an increased level of creatine phosphokinase in the blood serum and malondialdehyde in the brain structures were noted. The use of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide prevented the development of hyperenzymemia, dyslipidemia and corrected the increased level of creatine phosphokinase after 24 hours; in both modes of administration, it reduced the serum level of malondialdehyde. Piracetam showed little effect only when administered prophylactically, preventing an increase in serum alkaline phosphatase activity and cholesterol levels. Сonclusion. The revealed efficacy of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide and its previously studied complex mechanism of action suggest that 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide is a potential drug for the prevention of hypoxic disorders and acceleration of adaptation to high-altitude hypoxia.

Stress response is a multifactorial condition which is formed under extreme environmental exposure due to various neuroendocrine systems interactions. Dopaminergic system plays a key role in stress response through the dopamine which effect is realized after binding with special dopamine receptors types D1-D5. Expression of these receptors varies in different tissues, organs and specific brain structures but there is a special interest in their genes expression level in peripheral blood that can be served as additional marker to evaluate the chronic stress degree. Herein we determine the influence of various types induced chronic stress exposure during 6 months (such as exhausting physical activity (forced swimming), immobilization stress, and their combinations (swimming with immobilization)) on Drd1, Drd2 and Drd3 genes expression level in Wistar rats’ peripheral blood. According to our results, no activity for Drd2 and Drd3 genes is shown; however significant overexpression of Drd1 gene was detected in all studied groups after 3 months exposure compared to the data before experiment beginning, whereas after 6 months the relative expression level significantly decreased in the group with immobilization stress, which proves the negative effect of this type of chronic stress on the production of dopamine receptors of the D1 type. Thus, Drd1 gene activity in the blood can serve as a marker for assessing the severity of chronic stress in rats.

The toxic effects of multiwalled carbon nanotubes (MWCNTs) in mammals are important to assess due to MWCNTs are a widespread environmental pollutant. MWCNTs were tested for the effect on the behavioral functions of laboratory mice in the open field, rotarod, and elevated plus maze tests. Two possible routes of MWCNT entry into the body were examined: intrapharyngeal aspiration and intravenous administration, in order to model the most common ways of MWCNT entry, through the lungs and by assimilation from the blood through blood–tissue barriers. The potential toxin was administered once intrapharyngeally at 20 μg per mouse or intravenously at 0.2 μg per mouse. Acute and delayed effects were evaluated 24 h and 30 days after administration. Latent emotional tension and weaker exploratory reactions were observed 24 h after intrapharyngeal MWCNT aspiration. Signs of stress were still detectable 30 days after exposure. In contrast, an increase in locomotor and exploratory activities was observed 24 h after intravenous MWCNT administration. The result was explained by an inhibitory MWCNT effect on the lower respiratory tract and a potential lack of MWCNT accumulation in organs because MWCNTs were relatively large in size and could not penetrate through blood–tissue barriers.

The review deals with modern factors of the etiology and pathogenesis of autism, which is part of the autism spectrum disorder complex, approaches to the diagnosis and rehabilitation of patients, as well as social and humanitarian aspects of understanding this pathology as a phenomenon. Despite the fact that so far there is no single etiological concept of the development of autism, a sufficient amount of information has been accumulated that allows talking about genetic theory as one of the main causes of its occurrence. The functions of the main genes in which mutations can lead to the development of autism are examined in more detail, and its genomic architecture is established to be heterogeneous, that is, it is determined by polymorphism in several genes at once, and the disorder is aggravated when polymorphisms are combined with external risk factors. Some current aspects of the diagnosis of autism are outlined, including the main criteria a persistent lack of social communication and social interactions, limited, repetitive forms of behavior, speech impairment. The main diagnostic questionnaires and rating scales used for the more accurate diagnosis and verification of autism spectrum disorders are presented. When considering the treatment and rehabilitation of patients with autism and other disorders of the autism spectrum, it was concluded that integrated approach including various methods of psychological, pedagogical and medical correction, as well as social adaptation and integration is the most effective. Studies in the social sciences are presented that examine autism spectrum disorders within the framework of social constructivism, the role of the social context in identifying and treating autism is shown, as well as the impact of medical discourse on stigmatization and discrimination of the autistic community. The approaches to the conceptualization of autism in the framework of the theory and movement of neurodiversification, representing autism as a form of biological diversity that requires a positive identity of autistic people and the recognition of their differences by society, are highlighted.

Thiosemicarbazides of diphenylphosphorylacetic acid and their cyclic derivatives have been synthesized. Functionalization of the obtained 1,2,4-triazole-3-thiones with ethyl 2-bromoacetate at the sulfur atom has been carried out, the obtained esters have been transformed into the corresponding hydrazides via hydrazinolysis. Preliminary pharmacological tests of the synthesized compounds have been performed.