Closely related to the subfamily of proapoptotic proteins is the antiapoptotic protein bcl-2, which acts as an intracellular blocker of the mitochondrial apoptotic pathway. By inhibiting the action of effector caspases, as well as blocking the release of AIF and cytochrome C, Bcl-2 prevents regulated cell death and ensures survival in conditions of damage. The study was performed on Wistar rats, which were subjected to gravitational overloads (9g) in the caudocranial vector for 5 minutes twice a day for 28 days. An immunohistochemical study using antibodies to bcl-2 in a group of rats with simulated hypertensive encephalopathy revealed a heterogeneous positive cytoplasmic reaction, mostly moderately expressed. In individual pyramidal neurons and glial cells, expression was mosaic in nature, where both dusty accumulation of IRM of weak intensity and deposits of more pronounced intensity were detected. Visually more intense staining was detected in neurons with deformed perikarya against the background of pronounced edema. Increased expression of bcl-2 was also manifested in an increase in the relative area of the IRM. In CA1 of rats of the study group, this the indicator increased by 3.9% compared to the control (p<0.01). The most significant increase in the relative area of bcl-2-positive material was detected in CA2 and CA4, increasing, respectively, compared to the control by 5.6% (p<0.01) and 5.7% (p<0.01). Higher activity of bcl-2 in the CA1 and CA3 zones may be one of the factors for the greater stability of CA2 and CA4 in relation to CA1 and CA3.

The aim of our study is to characterize the peculiarities of Nf-kb expression in the inner pyramidal layer of the motor cortex of the brain in experimental type 1 diabetes mellitus (DM 1). The study was performed on 5 groups of animals, each group included 10 female rats at 12 months of age. Immunohistochemical study of the inner pyramidal layer of the motor cortex revealed the following differences between the intact and untreated type 1 DM groups: in the untreated type 1 DM group, Nf-kb IRM expression was observed predominantly in the nuclei of damaged neurons in the form of clumps, while in the intact group – in the cytoplasm of intact perikaryons. In the intact group, IRM expression was detected in vertically located axons of neurons, while in the untreated type 1 DM group, no Nf-kb expression was detected in vertical segments. Specific changes were also observed in the pharmacorrection group: the pattern of immunohistochemical characterization of the aminalone, succicardium group was more in line with that of the intacta group. In the group of pharmacorrection with mefargin the picture was similar to the picture of type 1 DM without treatment.

The neuroprotective effect of a novel conjugate of hydroxybenzoic acid with glycine (C40) was investigated in a model of ischemic stroke in rats with chronic cerebral circulation insufficiency (CCCI). The study was conducted in two stages: first, CCCI was modeled by stenosing the common carotid arteries by 50 %, followed by a 60-minute middle cerebral artery occlusion (stroke) after 40 days. Compound C40 and the reference drug citicoline were administered for 10 days before stroke and for 3 days after. Further, neurological deficit (the Garcia and Combs D’Alecy scales), sensorimotor functions (Open Field test, Adhesive Removal test, and Rotarod test), cognitive impairments (Novel Object Recognition and Morris Water Maze tests), cerebral blood flow level, and endothelial function were evaluated. Animals receiving the test substances demonstrated a statistically significant reduction in neurological deficit, less pronounced motor coordination and sensorimotor function impairments, as well as fewer short-term and long-term memory deficits compared to the negative control group. The observed decrease in neurological deficit in the experimental groups was accompanied by improved endothelial function and increased cerebral blood flow. The neuroprotective effect of the novel hydroxybenzoic acid derivative with glycine (C40) was comparable to that of reference drug citicoline.

The aim of this study was to evaluate the effect of solid herbal extract of Primula Veris L. and comparison drugs phenotropil and mildronate on the physical performance of female rats after chronic alcohol intoxication (CAI). CAI was modeled by replacing drinking water for 6 months with a 10 % solution of ethyl alcohol with sucrose (50 g/l). At the age of 16 months, the “Rotarod performance test”, “The horizontal rope walking test” and “Forced swim test with weight load” were performed. After CAI, rats show a deterioration in coordination and motor activity, a decrease in muscle strength and aerobic-anaerobic endurance. Solid herbal extract of Primula Veris L., phenotropil and mildronate contributed to an increase in the physical performance of animals after CAI.

Целью работы явилось изучение кардиопротекторного действия производного гидр- оксибензойной кислоты, содержащего в своем составе нейроактивную аминокислоту, соединения A-3, и препарата сравнения милдроната у крыс с хронической сердечной недостаточностью. Хроническую сердечную недостаточность моделировали введением L-изопротеренола внутрибрюшинно утром и вечером в дозе 2,5 мг/кг в течение 21 дня, с последующим определением инотропных резервов сердца в условиях нагрузочных тестов, дыхательной функции митохондрий, активности антиоксидантной системы и морфологического состояния кардиомиоцитов. Анализ прироста показателей сокращения (+dP/dtmax, %), раслабления (–dP/dtmax, %) миокарда и давления в левом желудочке (мм рт. ст., %) показал, что в среднем в контрольной группе исследуемые показатели были в 6,9, 7,2 и 2,6 раз ниже, чем в интактной группе (p < 0,05). Соединение A-3 в дозе 8,8 мг/кг при внутрибрюшинном введении 1 раз в день в течение 21 дня и препарат сравнения милдронат в дозе 50 мг/кг оказывали кардиопротекторное действие, о чем говорит увеличение прироста скорости сокращения миокарда, расслабления миокарда и давления в левом желудочке в среднем в 4,1, 4,6 и 2,3 раза и 4,7, 4 и 2 раза, по сравнению с контрольной группой (p < 0,05). Прирост максимальной интенсивности функционирования структур на 5 и 30 секундах отмечался в среднем на 86,76 и 78,12 % в группе, получавшей соединение A-3, на 81,17 и 75,52 % в группе, получавшей милдронат, что статистически значимо больше, чем в контрольной группе, где прирост составил 18,15 и 12,68 % (p < 0,05). При анализе митохондриальной функции отмечается ухудшение в контрольной группе в 2,5 и в 2,6 (p < 0,05) раза показателя дыхательного контроля (V3/V4 I и II), по сравнению с интактной группой. Исследуемое соединение A-3 и милдронат ограничивают негативное влияние хронической сердечной недостаточности на дыхательную функцию митохондрий: в группе, получавшей соединение A-3, в 1,9 и 1,8 раза и в группе, получавшей милдронат, в 1,7 раза, по сравнению с контрольной группой (p < 0,05). В контрольной группе концентрация малонового диальдегида была выше в 6,5 раз, активность супероксиддисмутазы ниже в 1,5 раза, по сравнению с интактной группой (p < 0,05). Исследуемое соединение A-3 и милдронат способствовали снижению концентрации малонового диальдегида в 2,5 и 1,7 раза и повышению активности супероксиддисмутазы в 2,4 и 2,1 раза, соответственно, по сравнению с контрольной группой (p < 0,05). Морфометрический анализ кардио- миоцитов показал, что соединение A-3 не оказывало влияния на исследуемые показатели, по сравнению с контрольной группой. У крыс, получавших милдронат, отмечалось уменьшение площади поперечного сечения и площади ядер кардиомиоцитов на 20 % на 30 % соответственно, по сравнению с контрольной группой (p < 0,05).

In experiments on adult rats, females studied the effect of a new derivative of GABA – citrocard (citrate of 4-amino-3-phenylbutanoic acid) on sexual behavior and fertility. Citrocard in doses of 50 mg/kg (experimentally proven therapeutic dose) and 700 mg/kg (dose exceeding the therapeutic 14 times) was administered intragastrically to female rats for 2 weeks. It was established that after the introduction of sexual behavior in rats of females receiving a citrocard at a dose of 50 mg/kg, the duration of sexual activity did not change relative to the control, but the ability to mate with males was clearly increased (“emotional” approaches and lordoses increased by 43,8 % (p 0.01) and 30.4 % (p 0.05)), respectively. In females treated with a citrocard at a dose of 700 mg/kg, the duration of sexual activity decreased slightly, but their receptive ability was higher than the control values (the number of lordoses indicating their readiness for mating increased by 17.4 % (p 0,05). It was also revealed that when mating with intact males in rats of females previously treated with a citrocard 2-week course, fertility processes and fertility rates increased. Relative to control, in females of the experimental groups, the pregnancy index increased, by 4.8% (p 0.05) and 33.3 % (p 0.05), respectively, in doses and fertility, by 4.2% (p 0 05) and 19.0% (p 0.05), as well as their overall fetal death rates decreased, both preimplantation and postimplantation.

In the process of aging, there is a general decrease in the physiological functions of the body, including cognitive ones. Cognitive abilities are a decisive factor in determining the quality of life of older people. 2 groups were formed: group 1 - rats at the age of 12 months (n = 10), group 2 - rats at the age of 24 months (n = 10). The degree of expression of synaptophysin and the relative area of the immunoreactive material in the dorsal and ventral hippocampus were determined. Immunohistochemical study using antibodies against synaptophysin in 12- and 24-month-old animals revealed a crescent-shaped distribution of immunoreactive material in the neuropil of the pyramidal layer CA1-CA4 of the dorsal hippocampus, most pronounced in old animals. In 24-month-old animals, an increase in the degree of expression of the immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed. In 12-month-old animals, in the neuropil of the pyramidal layer in CA1 and CA3 of the ventral hippocampus, a high degree of orderliness was found in the arrangement of dendrites in the radial layer and the distribution of immunoreactive material over the surface of the dendrites in the pyramidal and radial layers of the hippocampus, the most pronounced in CA1. At the same time, no age-dependent increase in the degree of expression of the immunoreactive material was found in the ventral hippocampus. We also did not reveal a significant increase or decrease in the relative area of the immunoreactive material in either the dorsal or ventral hippocampus. During aging in rats at the age of 24 months, an increase in the degree of expression of synaptophysin-immunoreactive material in the neuropil of the pyramidal, radial and molecular layers CA1 and CA3 of the dorsal hippocampus was revealed, which may be associated with the redistribution of synaptic vesicles in the presynaptic part of the synapses with their predominant localization in the presynaptic membranes, which determines the increase in the degree of expression of synaptophysin.

Studying of various forms of NO-synthases is of great interest, since they are involved in many of the mechanisms of neuronal injury, aggravating the ischemic cascade and negatively affect the clinical status of cerebrovascular diseases. Impaired functioning of NO synthase plays an important role in the progressing of neurodegenerative diseases, since nitric oxide is a modulator of neuroplasticity. Chronic cerebrovascular disorder was modeled on rats by the method of overloading in the caudo-cranial vector with a force 9 G for 5 minutes with an interval of 12 hours for 28 days. The level of iNOS expression was assessed by calculating the relative area of the immunoreactive material. The heterogeneity of the distribution of the immunoreactive material was expressed both in dust-like cytoplasmic accumulation and in the presence of small-lumpy deposits of iNOS-positive material in the neurons of the pyramidal layer and in the neuropil, and in glial cells the intensity of expression was more pronounced, reaching a pronounced one. The relative area of iNOS-positive material increased most significantly in CA3, by 8.3% (p<0.001), amounting to 12.1% [9.8;14.3]%. In CA1, the increase in the same indicator relative to the control was 3.9% (p<0.001), reaching 5.7 [4.5;6.1]%. In CA2 and CA4, respectively, the increase in the relative area of the IRM was 4.5% (p<0.05). We presume that the pronounced neuronal injury that is observed in the chronic cerebrovascular disorder modeling is a factor in the disruption of the hematoencephalic barrier, leading to edema, the subsequent acquisition of a pro-inflammatory phenotype by astrocytic and microglia and the switch from the constitutive type of NO-synthesis to the predominantly inducible type associated with activation of iNOS.

Background and aim: Chronic alcohol intoxication (CAI) induces heart damage. One of the promising ways of its treatment involves the administration of herbal medicinal products. The purpose of this study was to explore the effect of solid herbal extract of Primula veris L. (PVSHE) on the morphofunctional changes in rats' myocardium after CAI. Experimental procedure: CAI was simulated for 24 weeks. Loading testing was used to assess the functional condition of the heart, the functional assessment of mitochondria was based on the polarographic determination of oxygen consumption rate and determination of the indices of lipid peroxidation and antioxidant enzymes activity. We performed a microscopic examination of the left ventricle following the standard protocol of histological processing and h&e staining. Results and conclusion: PVSHE restricts the toxic effects of ethanol on the heart which was indicated by a higher rise in the rates of myocardial contraction (by an average of 3.9 times, P < 0.05) and relaxation (2.6 times under volume load, P < 0.05), LVP (by an average of 1.7 times, P < 0.05) and MISP (by an average of 1.5 times, P < 0.05). PVSHE caused an improvement in the functional state of rats' cardiac mitochondria exposed to CAI, which was demonstrated by on average 1.3-1.4 times (P < 0.05) as high RCR as compared to the control group. The histological examination of the myocardium of the animals treated with PVSHE showed the increase in the volume fraction of cardiac myocytes, and a 31.2% (P < 0.05) decline in the interstitial volume. Therefore, PVSHE has a protective effect on the heart after CAI. (c) 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype.

Введение: Гамма-аминомасляная кислота (ГАМК) и ГАМК-ергические соединения в последние годы рассматриваются как потенциальные средства для лечения сахарного диабета и его осложнений. Помимо основной тормозной функции в мозге, ГАМК также является сигнальной молекулой в островках поджелудочной железы (ПЖ), оказывая влияние на секрецию инсулина и глюкагона, а также апоптоз, выживаемость бета-клеток и их регенерацию. Цель: Сравнить защитное действие на β-клетки поджелудочной железы у ГАМК и ее новых производных у животных возрастом 18 месяцев с продолжительным стрептозотоцин-никотинамид-индуцированным сахарным диабетом. Материалы и методы: Сахарный диабет моделировали белым аутбредным крысам-самцам (12 месяцев) посредством введения комбинации стрептозотоцина (65 мг/кг) и никотинамида (230 мг/кг). В течение последующих 6 месяцев осуществлялся контроль уровня гликемии каждые 4 недели. Далее для исследования были отобраны животные с уровнем постпрандиальной гликемии между 11 и 18 ммоль/л. После формирования групп, в течение 1 месяца животные соответственно получали ГАМК и ГАМК-ергические соединения (композиция 2 и 3), контрольная группа получала физиологический раствор. После лечения был выполнен пероральный тест на толерантность к глюкозе. Далее был произведен забор образцов крови и тканей ПЖ (селезеночная часть) для иммуноферментного анализа (уровень ГПП-1, TNF-α в сыворотке и уровень NF-Κb,Nrf2, Клото в гомогенате ПЖ), иммуногистохимического анализа (экспрессия NF-Κb, Nrf2 и Клото в островках ПЖ) и иммунофлуоресцентного анализа (экспрессия инсулина и глюкагона в островках ПЖ). Результаты: Результаты исследования подтверждают выраженный гипогликемический эффект изученных производных ГАМК у животных возрастом 18 месяцев с продолжительной гипергликемией. Гипогликемическое действие исследуемых композиций сопровождалось увеличенной продукцией ГПП-1, улучшением функции и массы β-клеток ПЖ. Кроме того, повышенные уровни белка Клото и транскрипционного фактора Nrf2, а также подавление транскрипционного фактора NF-κB после лечения, могут играть ключевую роль в защитном действии исследуемых ГАМК-ергических соединений в отношении β-клеток. Заключение: Новые производные ГАМК обладают значительным защитным эффектом для β-клеток ПЖ. Эффекты могут быть обусловлены увеличенной на фоне их введения продукцией ГПП-1, белка Клото и транскрипционного фактора Nrf2, а также подавлением транскрипционного фактора NF-κB. Эти результаты подчеркивают потенциал ГАМК-ергических соединений в качестве средств для лечения сахарного диабета и его осложнений.

Excessive influence of glutamate on NMDA receptors mediates a cascade of biochemical changes leading to the development of intracellular acidosis, accumulation of free intracellular calcium and activation of a number of enzymes with the formation of free radicals. D-serine acts as a co-agonist of NMDA receptors and is involved in learning and memory under normal conditions. However, it has been suggested to play a role in glutamate damage in a number of CNS diseases. The formation of D-serine in neurons and glial cells occurs with the participation of the enzyme serine racemase (SR) from L-serine. An increase in the content of SR and the product of its enzymatic reaction, D-serine, is considered as a process preceding excitotoxicity. Hypertensive encephalopathy was modeled on 12-month-old rats by the method of exposure to negative longitudinal g-forces in the caudocranial vector with a force of 9 G for 5 minutes with an interval of 12 hours for 28 days. The following indicators were assessed: behavioral responses, cognitive and mnestic functions, the relative number of neurons with signs of damage, and the level of expression of serine racemase. A morphometric study of the pyramidal layer of the hippocampus revealed a significant increase in the relative area of the immunopositive material in CA1 by 5.5% compared with the control (p<0.05). A feature of the expression of serine racemase in the experimental group was the translocation of immunopositive material, which was determined not only in the cytoplasm of perikaryons, but also in the dendrites of pyramidal neurons. In addition, the nature of expression changed in the experimental group to a moderately pronounced one, and in some pyramidal neurons to a pronounced one. Violation of the cytoarchitectonic of the CA1 zone was manifested in a less compact arrangement of pyramidal neurons, a pattern of spongiosis due to pericellular and perivascular edema, and the acquisition of increased tortuosity by neuronal dendrites. Hypertensive encephalopathy modeling demonstrates a sharp increase in the relative number of neurons with signs of damage, a decrease in the specific

Целью исследования являлось изучение эндотелиопротективного действия ГАМК и ее нового производного — композиции МФБА, состоящей из гидрохлорида метил-4-амино-3-фенилбутаноата и гидрохлорида L-аргинина в соотношении 1:1, в условиях длительной гипергликемии. В качестве модели использовали крыс Вистар (12 мес) с 6-месячным стрептозотоцин-никотинамид-индуцированным сахарным диабетом. Проводили глюкозотолерантный тест и распределяли животных на группы, которым в течение 4 недель внутрь вводили ГАМК и композицию МФБА. Далее оценивали уровень гликемии, суточную протеинурию, функциональное состояние эндотелия: его вазодилатирующую, антитромботическую функцию, уровень фактора фон Виллибранда (vWF) и количество циркулирующих эндотелиальных клеток в крови. Методом ИФА в плазме крови определяли содержание ряда маркеров, в большей степени влияющих на развитие осложнений сахарного диабета (белок Клото, BDNF, Nrf2, ФНО-α и iNOS). Показано, что длительная гипергликемия приводила к формированию эндотелиальной дисфункции, которая проявлялась снижением эндотелийзависимой вазодилатации и антитромботической функции эндотелия, увеличением в крови циркулирующих эндотелиальных клеток и уровня vWF, а также суточной протеинурии. В плазме наблюдалось снижение содержания белка Клото, BDNF, Nrf2 и повышение содержания провоспалительных факторов ФНО-α и iNOS. Курсовое введение ГАМК и МФБА приводило к снижению гликемии и значительному улучшению вазодилатирующей и антитромботической функции эндотелия, повышению плазменного уровня белка Клото, нейротрофического фактора BDNF и транскрипционного фактора Nrf2, а также снижению ФНО-α и iNOS. По сравнению с ГАМК ее производное — композиция МФБА оказывала более выраженное действие в меньшей дозе (20 мг/кг в сравнении с 1000 мг/кг). Таким образом, производное ГАМК — композиция МФБА при длительной гипергликемии, помимо гипогликемического, оказывает выраженное эндотелиопротективное действие, улучшая вазодилатирующую и антитромботическую функции эндотелия и снижая содержание провоспалительных факторов ФНОα, iNOS и количество циркулирующих эндотелиальных клеток, что указывает на ее возможный высокий потенциал в качестве средства для профилактики сосудистых осложнений сахарного диабета.

It has been suggested that NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) activation is a critical trigger for functional impairment and damage to pancreatic -cells in type 2 diabetes mellitus (DM). In this work, using the immunohistochemical method, we studied the effect of aminalon and picamilon on the early modulation of NLRP3 inflammasome activity during experimental alloxan-induced DM in laboratory rats. Per os administration of aminalon (500 mg/kg) and picamilon (250 mg/kg) for 5 days before the administration of alloxan and for 2 days after the injection, suppression of NLRP3 activity was noted, as indicated by a significant decrease in the area of immunopositive pancreatocytes to (21,30 5,44) and (39,31 5,24) %, respectively, relative to the value in the group of animals that were not treated (75,197,69%). The results of the study showed that the studied preparations with GABAergic action promoted correction of functional disorders of the pancreas during alloxan-induced DM by inhibiting activation of NLRP3 inflammasome in pancreatocytes.

In experiments, in female rats, the novel substance dipiarone with hypoglycemic activity when administered intragastrically at doses of 0.5 mg/kg and 100 mg/kg from 6 to 16 days of gestation did not have a damaging effect on the processes of organo- and fetogenesis and did not contribute to the occurrence of deformities and abnormalities in the development of fetuses recorded in the antenatal and postnatal period of their development. Intragastric administration of dipiarone to rats at a dose of 100 mg/kg from 6 days of pregnancy until delivery showed that the formation of physical development of rat offspring in the postnatal period corresponds to the control parameters, while they had an increase in the rate of body weight gain, ahead of the time of formation of sensory-motor reflexes, activation of motor and emotional behavior.

Introduction: Gamma-aminobutyric acid (GABA) and GABAergic compounds emerged as potential therapeutic agents for diabetes mellitus and its complications. GABA acts as an inhibitory neurotransmitter in the central nervous system and as an extracellular signaling molecule in pancreatic islets, exerting beneficial effects on insulin secretion, glucagon production, apoptosis, beta-cell survival, and regeneration. Aim: This study aimed to compare the efficacy of GABA and GABAergic compounds as pancreatic β-cell protective agents in aged rats (18 months) with prolonged hyperglycemia induced by streptozotocin-nicotinamide injection. Materials and Methods: Male outbred albino rats aged 12 months were intraperitoneally injected with streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Over the next 6 months, the level of glycemia was monitored every 4 weeks. Further, rats with postprandial glycemia levels between 11 and 18 mmol/L were selected. The experimental groups were treated with GABA and GABAergic compounds (compositions 2 and 3) for 1 month, while the control group received saline. An oral glucose tolerance test (OGTT) was performed after treatment. Blood and samples of the pancreatic tissue (splenic part) were collected for enzyme-linked immunosorbent assay (GLP-1, TNF-α serum level and NF-κB, Nrf2, Klotho tissue homogenate level), immunohistochemistry (islet NF-κB, Nrf2 and Klotho protein expression) and immunofluorescence assays (islet insulin and glucagon expression). Results: The research findings demonstrate significant hypoglycemic effects of the studied GABA derivatives in aged rats with prolonged hyperglycemia. These GABA derivatives effects were accompanied with increased GLP-1 production and improved pancreatic β-cell function and mass. Furthermore, elevated levels of Klotho protein and Nrf2 transcription factor, along with the suppression of NF-κB transcription factor after treatment, may play a crucial role in the β-cellprotective effects of these GABA derivatives. Conclusion: Novel GABA derivatives exhibit significant pancreatic β-cell protective effects that may be mediated by enhanced GLP-1, Klotho protein, and Nrf2 transcription factor, and suppressed NF-κB transcription factor. These results highlight the potential of GABA derivatives as promising therapeutic agents for managing diabetes mellitus and its associated complications.

The development of original drugs is a complex, time-consuming, labor-intensive, costly, and risky process. The pharmaceutical industry is a critically important area of technological sovereignty of the country. Effective functioning of the drug supply system is impossible without original drug development process, which provide the foundation for progressive evolution of a number of branches of the socio-economic sector of the countrys economy. Domestic pharmacology faces several unresolved problems, many of which must be viewed through the prism of pharmacological disciplines, primarily theoretical and clinical pharmacology, and considering the evolution of approaches used in them. Pharmacology is a system of thought for pharmacologists and experts in drug development, aiming not only to improve the quality and quantity of drugs created, but also to accelerate this process. This article describes the essence of the pharmacological approach, briefly describing the main stages of the development of an original drug from the idea to research conducted, after the widespread introduction of the drug into clinical practice. At the end of the article the authors presented the successful experience of pharmacological approach application by pharmacologists of Volgograd State Medical University on the example of the development of an original drug for the treatment of diabetes mellitus and its complications.

Diabetes mellitus (DM) is the leading cause of premature death and disability. Despite a significant number of drugs, the effectiveness of therapy aimed at normalizing the level of glycemia and preventing complications does not fully satisfy doctors and patients. Therefore, the search for new approaches for the prevention and treatment of DM and its complications continues. Significant resources are used to develop new drugs, but recently the possibility of using «old» widely available drugs with newly discovered pleiotropic properties has been substantiated. These may include preparations of gammaaminobutyric acid (GABA) and agents that directly or indirectly activate GABAergic transmission, which have a pronounced pancreatic protective effect, which has been widely discussed in foreign literature over the past 10-15 years. However, there are few such publications in the domestic literature.It has been established that the content of GABA in β-cells in patients with type 1 and type 2 diabetes is reduced and this correlates with the severity of the disease. Genetic suppression of GABA receptors causes a significant decrease in the mass of β-cells and glucose-stimulated insulin secretion, which confirms the importance of GABA in ensuring glucose homeostasis and the advisability of replenishing the GABA deficiency in DM with its additional administration. It has been established that in animals with DM, GABA suppresses apoptosis and stimulates the regeneration of β-cells, increases β-cell mass and insulin production.Experimental data have been obtained indicating a synergistic effect of GABA when combined with glucagon-like peptide-1 (GLP-1) receptor agonists, DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, when a more pronounced pancreoprotective effect is observed, due to decrease in oxidative and nitrosative stress, inflammation, increase in the level of Klotho protein, Nrf-2 activity and antioxidant defense enzymes, suppression of NF-kB activity and expression of pro-inflammatory cytokines. As a result, all this leads to a decrease in apoptosis and death of β-cells, an increase in β-cell mass, insulin production and, at the same time, a decrease in glucagon levels and insulin resistance.The review substantiates the feasibility of using GABA and drugs with a positive GABAeric effect in combination with new generation antidiabetic agents: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors in order to increase their antidiabetic potential.The search was carried out in the databases Pubmed, eLibrary, Medline. Keywords: diabetes mellitus, gamma-aminobutyric acid, glucagon-like peptide-1, GLP-1 receptor agonists, glucose-dependent insulinotropic peptide, dipeptidyl peptidase inhibitors, sodium-glucose cotransporter 2 inhibitors. The search was carried out from 2000 to 2022, but the review presents the results studies published mainly in the last 3 years, due to the requirements of the journal for the maximum amount of work and the number of sources.

The heat shock protein (Hsp) system acts as intracellular chaperone molecules responsible for maintaining normal intracellular homeostasis by regulating the correct coagulation of newly synthesized peptides, as well as the transport and degradation of mature proteins. In addition to their role as chaperones, proteins of the Hsp family stabilize the cell membrane and inhibit the caspase-dependent apoptosis cascade Hypertensive encephalopathy was modeled on 12-month-old rats by the method of exposure to negative longitudinal overloads in the caudo-cranial vector with a 9 G force for 5 minutes with 12 hours interval for 28 days. The behavioral responses, cognitive and mnestic functions, the relative number of pyramidal neurons with hyperchromic cytoplasm and shrunken perikariya, and the level of expression of heat shock proteins 70 kDa (Hsp70) and 90 kDa (Hsp90) were assessed After 28 days of exposure to 9 G negative longitudinal overloads, the rats showed functional and morphological manifestations characteristic of hypertensive encephalopathy. There was a decrease in the basic reflexes, disorders of the cognitive sphere, as well as decrease in memory and orientation-exploratory activity. Morphological examination of the hippocampus against the background of pronounced edema revealed a significant increase in the relative number of pyramidal neurons with hyperchromatosis and perikaryon shrinkage in all zones of the pyramidal layer (p <0.01). These signs of reversible and irreversible damage were accompanied by a significant increase in Hsp70 expression, especially pronounced in the CA3 zone (p <0.01). A significant increase in Hsp90 expression was found in the CA1 zone (p <0.05) Discirculatory encephalopathy experimental modeling demonstrates signs of both reversible and irreversible alteration in all regions of the pyramidal layer of hippocampus. Differences in the ability of neurons of the pyramidal layer of different regions of the hippocampus to express Hsp70, Hsp90 were noted. In the CA1 and CA3 zones, compensatory reactions are more pronounced and are accompanied by a more pronounced expression of Hsp70, while in CA1, the expression of Hsp70 and Hsp90 is simultaneously enhanced