Assessment of fabomotizole effects on postnatal development of newborn and adult rat offspring after maternal ethanol or cigarette smoke exposure was performed. The experiments were carries out in outbred pregnant rats housed in the vivarium of FSBI “Zakusov Institute of Pharmacology”. Each group included at least 10 animals. Ethanol (4.3 ml/kg, 40 % vol.) was administered per os from 10 to 19 days of pregnancy; exposure to cigarette smoke from 4 cigarettes with filter (13 mg of tar and 1 mg nicotine) was performed throughout the pregnancy once a day. Fabomotizole (1 and 10 mg/kg, daily) was administered per os in all experiments. The unconditional reflexes formation and muscle strength were evaluated on postnatal day 5. The same animals were examined in the tests «T-shaped maze» and «extrapolation disposal» to assess cognitive functions after postnatal day 60. These studies demonstrated the ability of fabomotizole to prevent or reduce postnatal abnormalities of rats exposed to ethanol or tobacco smoke in utero. The results show the potential opportunity of using fabomotizole for prevention of delay physical development, learning and memory.

Problem statement. Diclofenac is considered a well-recognised reference drug in the study of the therapeutic effects and safety of non-steroidal anti-inflammatory drugs. Diclofenac works by inhibiting cyclooxygenase-1 and cyclooxygenase-2. However, no data about the effect of the drug on the level of histamine and serotonin, cellular mediators of inflammation, are available in the literature. The aim of this experimental study is to evaluate the level of histamine and serotonin in rats with acute exudative inflammation and to study the effect of diclofenac sodium on their concentration. Materials and methods. The study was performed in male outbred white rats. Peritonitis induced by intraperitoneal injection of 1 % acetic acid was used as a model of acute exudative inflammation. The concentration of histamine and serotonin in blood plasma and peritoneal exudate was determined by fluorometry. Results. Three hours after the acetic acid injection, the concentration of histamine in the plasma of rats was elevated by a factor of 1.9 (p < 0.05), and the concentration of serotonin was increased threefold (p < 0.05). A single oral dose of 6.3 mg/kg Diclofenac sodium was administered one hour before the onset of inflammation. The test drug significantly reduced histamine levels in the plasma of rats with acute exudative inflammation but had no effect on serotonin levels. Diclofenac sodium did not change the concentration of the inflammatory mediators in the exudate of animals with the experimental pathology. Conclusion. The ability of diclofenac sodium to reduce elevated histamine levels in the plasma of rats with experimental peritonitis may be one of the components of the mechanism by which this drug reduces vascular permeability and swelling.

Resume. Relevance. One of the actual problems facing modern medical science is the study of mechanisms and the search for effective ways to activate tissue neovascularization. A possible approach to the decision of this problem is the use of TrkA receptor agonists to activate angiogenesis and, as a consequence, improve the vascularization of ischemic tissues. The aim of this investigation was to study the angiogenic and antiischemic activity of the TrkA receptor agonist the nerve growth factor 4th loop dipeptide mimetic the GK-2 compound. Methods. Experiments were performed on models of hind limb ischemia and myocardial infarction in rats. The compound GK-2 (1 mg/kg) was administered intraperitoneally for 14 days. Effects were evaluated using light microscopy and two-dimensional echocardiography. Results. In the model of the hindlimb ischemia in rats, it was shown that GK-2 (1 mg/kg, i.p.) significantly enhances the vascularization of the ischemic sural muscle. The vascularization index of ischemic tissue in animals treated with GK-2 was almost 2 times higher than in control - 27794 (25218 t 35941) and 14725 (9030 t 19630), respectively (p < 0.001). According to light microscopy, the studied compound reduces the intensity of tissue damage. Under conditions of experimental myocardial infarction, the GK-2 compound reduces the pathological remodeling intensity of the heart left ventricle. Conclusion. It can be assumed that the antiischemic effect of GK-2 is associated with increased vascularization of the affected tissue, i.e. with the stimulation of angiogenesis.

Resume. Background. Today the search for drugs for alcoholism treatment is concentrated around substances with anticonvulsant action, which not only stop convulsive syndrome, but also contribute to the extension of the remission period during alcohol withdrawal. Despite the successful experience in the alcoholism treatment with structural analog GABA gabapentin, there is no convincing evidence of gabapentin interaction with GABA-ergic system in the brain, moreover, most results were obtained in vitro. The aim of the present work was to study mechanism of gabapentin action on CNS and its interaction with ethanol using electrophysiological methods in vivo. Methods. The effect of gabapentin on electrical activity of neurons in the frontal cortex of rats was studied with the microelectrode technique in adult male Wistar rats. Results. Gabapentin after systemic administration, 25-100 mg/kg, i.p., dose-dependent reduced the frequency of action potentials (AP) of neurons, without changing amplitude and shape of AP of neurons. When assessing changes in the frequency of extracellular exhaust AP at microiontophoretically summing gabapentin it is established that the drug reduced the frequency of АP in 15 of 23 neurons (p < 0.05), and increased GABA-induced inhibition of pulsed electrical activity of neurons in the frontal cortex. Gabapentin didn’t affect the magnitude of exiting responses on ethanol supplied to neurons, however, increased (p < 0.05) inhibitory responses caused by ethanol in all 45 of the cells studied. Conclusion. The obtained data suggest that gabapentin has an allosteric effect on postsynaptic GABA receptors and increases ethanol-induced inhibition of neurons of the frontal cortex.

Resume. Relevance. Alcoholic cardiomyopathy (ACM) is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. Their underlying mechanisms are poorly known, leading to a lack of effective therapy. Related with oxidative stress DNA damage and cell death play an essential role in the development of alcoholic cardiomyopathy. The aim of present study - using previously developed translation model to evaluate the levels of DNA damage and apoptosis in the myocardium of rats with ACM and modulating effect of cardioprotective drugs. Methods. ACM was established by forced alcoholization of rats (10 % ethanol solution as the only source of drinking water for 24 weeks; mean daily ethanol consumption was 5.0-6.5 g/kg). Trimetazidine (20 or 30 mg/kg), fabomotizole (15 mg/kg) or their combination (20 + 15 mg/kg) were injected ip, daily during following 4 weeks of abstinence. DNA damage was evaluated using alkaline and neutral comet assay. Apoptosis was assessed by TUNEL assay in paraffin-embedded sections. Results. No DNA damage or apoptosis of the myocardial cells was observed in rats with alcoholic cardiomyopathy at the abstinence period. A decrease in the level of cardiomyocytes with a high degree of DNA fragmentation, referred to as “hedgehog” DNA comets and that are presumably cells at the stage of autophagic fragmentation of chromatin, was revealed. Treatment of rats at the abstinence period with cardioprotective drugs trimetazidine and fabomotizole or their combination raised “hedgehog” DNA comets level up to control value. Conclusion. Our findings allows considering the appearance of cardiomyocytes with highly fragmented DNA as an important mechanism for regulating and maintaining myocardial homeostasis in ACM.

Resume. Different cell types respond differently to the effects of vitamin D₃. The paper presents the results of a dose-dependent differential chemotranscriptome analysis of vitamin D₃ in relation to breast tumor cells (MCF7 line) and neuron progenitor cells (NPC line). Expression of the genes involved in immunomodulation (192 genes) was significantly increased in tumor cells and in the intracellular signaling from receptors (275 genes) and the expression of genes involved in maintaining energy metabolism (482 genes), cell division / proliferation (387 genes), DNA repair (391 gene), synthesis and transport of proteins (188 genes) and in maintaining chronic inflammation (factors of TNF / NF-kB. 105 genes). In neuronal cells, similar changes in the expression of these categories of genes occurred to a much lesser extent and did not reach statistical significance. The reduction in DNA repair in tumor cells stimulates their apoptosis, the decrease in energy metabolism reduces the ability of tumor cells to divide and to resist therapeutic effects. It is interesting to note that vitamin D₃ contributed to a decrease in the expression of genes supporting the cellular response to gamma radiation (9 genes) and contributed to the enhancement of the antitumor effects of vitamin A (5 genes). Also, vitamin D3 reduced the expression of genes that express potential target proteins of antitumor drugs (casein kinase, c-src tyrosine kinase, c-myc, etc.). Thus, vitamin D₃ suppressed the division of tumor cells in a dose-dependent manner, without adversely affecting the survival of neurons.

Resume. Comparison of “concentration-effect” relation for a new potential anxiolytic drug GML-1, being TSPO Ligand was carried out. GML-1 was administered in rats once, intragastricaLLy in the dose 1 mg/kg. Tested drug concentrations in the rat bLood plasma and animaLs behavior in the test of “eLevated pLus maze” were evaLuated. A vaLue of GML-1 anxioLytic effect does not correLate to concentration in the rat bLood pLasma.

Resume. The purpose of this investigation is to study the adequacy of the echocardiography method in small laboratory animals for performing acute pharmacological tests. In experiments on white mongrel male rats, a nonselective ß-adrenoreceptor agonist isoproterenol (20 μg /kg, i.v.) reduces the end-systolic and end-diastolic dimensions and volumes of the heart left ventricle, measured by echocardiography, and increases the shortening and ejection fractions, i.e. has a positive inotropic effect. Cardioselective ß1-adrenoblocker metoprolol (1 mg / kg, i.v.), on the contrary, increases the left ventricle sizes and reduces the shortening and ejection fractions, i.e. has a negative inotropic effect. Thus, the method of echocardiography in small laboratory animals can be used to conduct acute pharmacological tests.

Resume. Relevance. The acute toxicity evaluation is the anecessary stage of preclinical research of the new original anxiolytic drug GML-1. The present investigation aim is study of the GML-1 acute toxicity. Methods. GML-1 was administered once orally and intraperitoneally to mice and rats in the maximum possible volumes for each of the administration methods and for each animal species, at the highest possible concentrations. Equivalent volume of 1 % starch solution was administered to animals of the control groups. Euthanasia and pathoanatomical dissection were performed 14 days after the drug administration. The animal intoxication periods with a detailed description of the observed clinical picture were registered. Results. The mean lethal doses were not identified because GML-1 did not cause death of animals at injection of the maximum allowable volumes and maximum allowable concentrations. The morphological view of the internal organs, detected during pathoanatomical dissection of all experimental animals, did not differ from that observed in control animals. Conclusion. It was determined that the drug GML-1 at oral and intraperitoneal injection concerns to low-toxic substances. According to classification Sidorov K.K. (1973) this drug may be related to 4th toxicity class.