The progressive nature of type 2 diabetes mellitus leads to the need for insulin therapy in a significant proportion of patients. Very often start of insulin therapy in type 2 diabetes mellitus (T2DM) is associated with weight gain and a significant increase of hypoglycemia’s risk. However, innovative options, such as fixed ratio combinations of glucagon-like peptide 1 receptor agonists (GLP-1RA) and basal insulin, minimize weight gain and hypoglycemia risks and allow a greater proportion of patients to achieve individual glycemic control goals without compromising safety parameters. This review includes a description of the randomized clinical trials, as well as the results of real clinical practice of the use of two currently existing fixed ration combinations of GLP-1RA and basal insulin — iDegLira and iGlarLixi.

Modern requirements for the treatment of type 2 diabetes mellitus (DM2) include not only achieving a glycemic control, but also reducing the risk of developing cardiovascular complications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are inferior in the effectiveness to some other actively developing groups of hypoglycemic drugs (SGLT2 inhibitors and GLP-1 receptor agonists); however, they seem relevant at the present time.The aim of the study is to analyze the literature data on the therapeutic potential and results of the of DPP-4 inhibitors research.Materials and methods. When searching for the review article materials, the abstracting databases of PubMed, Google Scholar and e-Library were used. The search was carried out on the publications for the period from 2006 to 2022, using the following keywords: DPP-4 inhibitors; glucagonlike peptide-1 (GLP-1); glucose-dependent insulinotropic peptide (GIP); sitagliptin, and other drugs.Results. DPP-4 belongs to the serine proteases family and is involved in the degradation of various chemokines and peptide hormones, including incretins secreted by intestinal L- and K-cells – GLP-1 and GIP. They regulate a postprandial insulin secretion and a β-cell function, modulate a fasting and postprandial glucagon secretion, regulate the eating behavior and have many pleiotropic (immunomodulatory, anti-inflammatory, antifibrotic, etc.) effects. DPP-4 inhibitors reduce an enzyme activity by 70–90%, increasing plasma incretin levels by 2–4 times and have been used to treat DM2 since 2006. Now there are 13 DPP-4 inhibitors on the market in different countries, differing primarily in pharmacokinetic parameters. They are actively used in the combination therapy for type 2 diabetes, increasing the glycemic control effectiveness without increasing the risk of hypoglycemia. The evidence is emerging about the therapeutic potential of DPP-4 inhibitors in COVID-19.Conclusion. A peroral form, an ability to create effective combinations with other hypoglycemic drugs without increasing the risk of hypoglycemia, the pleiotropic effects of DPP-4 inhibitors, make this group relevant at the present time.

AIM: The work aimed to investigate inducible NO synthase (iNOS) expression in dentate gyrus in mature rats when modeling depression, as well as the establish the pharmacological correction possibility of detected changes with Phenibut and compounds under laboratory codes of RSPU-189, RSPU-135. MATERIALS AND METHODS: Depressive-like behavior in animals was modeled by combining stressful stimuli such as loud sound, pulsating bright light, and vibration simultaneous with constant restriction of mobility and fluctuations in temperature of environment for 7 days (daily for 30 minutes). Changes in level of iNOS expression in dentate gyrus were assessed by calculating relative area of immunoreactive material (IRM) and staining intensity in points from 0 to 3. RESULTS: Compared with the control group, rats with experimental depression showed an increase in expression of iNOS-IRM in cytoplasm of neuronal perikarya in granular layer of dentate gyrus, as well as an increase in relative area of iNOS-IRM in neuropil and nerve cells. The use of the compound RSPU-189 (salifen) demonstrated to a greater extent the corrective effect, since in the cytoplasm of neuronal perikarya in granular layer of dentate gyrus of rats, there was a decrease in the expression of iNOS-IRM, as well as a decrease in the relative area of iNOS-IRM in neuropil and nerve cells, which corresponded to values of these parameters in the control group of animals. CONCLUSIONS: An experimental modeling of depression in dentate gyrus of mature rats revealed an increase of iNOS-IRM expression, the decrease of which was noted in its pharmacological correction with the compound RSPU-189 (salifen), which may indicate the predominant neuroprotective effect of this compound on GABAergic neurotransmission mechanisms.

From derivatives of quinazolin-4 (3H) -one, 2 substances were isolated: VMA-13-15 (N-[2-[4-oxo-3(4H)-quinazolinyl] propionyl]guanidine) and VMA-13-17 (N-[2-[6-bromo-4-oxo-3(4H)-quinazolinyl]acetyl]guanidine). With the therapeutic administration of the compounds, the survival rate and neurological condition of animals with bilateral occlusion of the common carotid arteries were better than in the control group. Also 72 hours after surgery and treatment, the level of cerebral blood flow and the severity of the reactions of cerebral vessels to the introduction of a stimulant and a blocker of nitric oxide synthesis were higher. Compounds VMA-13-15 and VMA-13-17 are promising for further study of their therapeutic potential in cerebrovascular accidents.

Depression is one of the leading causes of declining working capacity in the population and remains one of the most common mental disorders in the world in all age groups. The features of the expression of endothelial NO-synthase in the dentate gyrus in mature rats were assessed when simulating a depressive state, as well as the possibility of pharmacological correction of the revealed changes with phenibut. Evaluation of changes in the level of expression of immunoreactive material in the dentate gyrus was determined in the granular and subgranular layers by assessing the intensity of staining in points from 0 to 3. In rats with an experimental depression, compared with the control group, there was a decrease in the degree of expression of immunoreactive material in the dentate gyrus. The use of phenibut contributed to the correction of the studied signs.

In experiments on outbred male beauty 4 months of age, the effect of the new compound ZB-16 (GPR 119 receptor agonist), with hypoglycemic activity [6], on spermatogenesis and fertilizing function was studied. Compound ZB-16 was administered intragastrically to animals of the experimental groups for 2 months (equivalent to one spermatogenesis cycle) in doses: 0,5 mg/kg (experimental therapeutic dose) and 100 mg/kg (higher dose than 200 times the therapeutic dose), the control group of males was intragastrically injected with a solvent of the compound - distilled water. It was found that under the influence of ZB-16, in males in both experimental groups, the spermatogenesis index is moderately increased (by 3,0 %, p > 0,05), the total number of spermatozoa (by 44,4 %, p > 0,05 and 19,2 %, p > 0,05, respectively, the 1st and 2nd experimental groups), the number of tubules with desquamated epithelium decreases, and the number of pathological forms of spermatozoa and the number of tubules with 12th stage of meiosis are not changed. According to the results of mating of the studied groups of males with intact females, a clear tendency towards an increase in the pregnancy index and a decrease in the post-implantation death of the embryos is revealed in the females relative to the control.

На крысах линии Вистар с экспериментальным сахарным диабетом изучена гипогликемическая активность новых агонистов рецепторов глюкагоноподобного пептида-1 (GPR119). После определения уровня гликемии и формирования групп (в исследование включали животных с уровнем гликемии в пределах 10 – 18 ммоль/л) исследуемые агонисты GPR119 (ZB-16, ZB-17, ZB-18 и ZB-20) вводили в течение 4 недель в 3 дозах (0,1; 1 и 10 мг/кг внутрижелудочно с помощью зонда). Гипогликемическую активность соединений оценивали через 7, 14 и 28 дней применения по уровню глюкозы в плазме крови натощак (после 6 ч голодания), а также скорости ее утилизации при проведении перорального теста на толерантность к глюкозе (ПТТГ). В качестве препаратов сравнения применяли метформин (400 мг/кг) и ситаглиптин (10 мг/кг). Курсовое введение исследуемых агонистов GPR119 сопровождалось снижением уровня гликемии натощак и увеличением скорости утилизации глюкозы по данным ПТТГ. Наиболее выраженным гипогликемическим действием обладало соединение ZB-16 в дозе 1 мг/кг, при этом значимый эффект наблюдали уже через 7 дней введения. Выраженность гипогликемического действия ZB-16 через 28 дней применения была сопоставима с таковой в группах крыс, получавших метформин и ситаглиптин. Таким образом, агонист рецепторов GPR119 — соединение ZB-16 — в дозе 1 мг/кг при 4-недельном введении животным с экспериментальным сахарным диабетом оказывает выраженное гипогликемическое действие, значительно снижая уровень гликемии натощак и повышая скорость утилизации глюкозы при проведении ПТТГ.

Studies of morphofunctional changes in the hippocampus using a model of impaired cerebral hemodynamics are needed for understanding the mechanisms of formation of psychoneurological deficits. The aim of the present work was to assess CNS damage and the characteristics of the expression of one of the main regulators of apoptosis – Bcl-2 – in the hippocampus of rats with impaired cerebral hemodynamics induced by repeated gravitational overloading. The study was carried out on Wistar rats which were subjected to gravitational overloading (9 g) in the caudocranial direction for two 5-min periods each day for 28 days. Psychoneurological impairments in the animals were assessed using the McGraw scale and the open field, adhesion, conditioned passive avoidance reaction (CPAR), and escape extrapolation (EET) tests. Brain sections were stained by the Nissl method and the specific numbers of neurons with signs of damage were counted. Immunohistochemical studies of the level of Bcl-2 expression assessed the relative areas of immunoreactive material in the pyramidal layer in all hippocampal fields. Gravitational overloading induced impairments to the animals’ behavior, which was expressed as low movement activity and signs of retrograde amnesia, decreased fi ne motor function, and increases in psychoneurological deficit. Histological studies identified destructive changes to vessels and increases in the specific number of pyramidal neurons with damage in all fields of the hippocampus. Fields CA2 and CA4 showed the greatest increases in the numbers of damaged neurons, along with marked Bcl-2 expression.

BACKGROUND: Metabolic syndrome and obesity are often precursors of type 2 diabetes mellitus (DM), and current recommendations indicate the advisability of early initiation of drug therapy at the stage of prediabetes. Drugs with incretin activity are one of the priority groups for monotherapy of type 2 diabetes in the onset of the disease, and certain drugs are used to treat obesity. GPR119 agonists increase the secretion of endogenous incretins, and their effectiveness in the treatment of type 2 diabetes and obesity in mono- and combination therapy is currently being actively studied. AIM. To evaluate of the effect of administration of a GPR119 receptor agonist, its combination with metformin or sitagliptin on body weight, food intake and glycemia in rats under a high-calorie diet. MATERIALS AND METHODS: The study was conducted on 56 outbred female rats aged 7–8 months and an initial weight of 305–320 g. Compound ZB-16 is a highly active GPR119 receptor agonist (EC50 = 7 nM). For 12 weeks, the animals were kept on a high-fat and carbohydrate diet and at the same time received the compound ZB-16, metformin and sitagliptin, or its combination (ZB-16 + metformin and ZB-16 + sitagliptin). During the experiment, the weight of the animals, the mass of feed eaten, as well as the level of glycemia after 6 hours of fasting and with an oral glucose load were assessed. RESULTS: In animals of the control group that were on a high-calorie and fatty diet for 12 weeks, an increase in body weight, glycemia and a decrease in the rate of glucose utilization were observed. The introduction of the GPR119 agonist (ZB-16) for 12 weeks led to a significant reduction in the amount of food consumed, limited weight gain and prevented the development of carbohydrate metabolism disorders. The addition of sitagliptin and especially metformin to therapy with the GPR119 agonist significantly increased the effectiveness of therapy compared to the control group, which was expressed in the normalization of animal body weight and glycemia (p <0.05). CONCLUSIONS: The introduction of a combination of the GPR119 agonist (compound ZB-16) with metformin and sitagliptin is more effective than monotherapy in terms of weight gain, food intake, and also prevents the development of carbohydrate metabolism disorders in animals when kept on a high-fat and carbohydrate diet.

Сахарный диабет (СД) 2 типа значительно повышает риск развития инсульта и выбор гипогликемической терапии может оказать влияние не только на вероятность развития, но и на тяжесть течения нарушения мозгового кровообращения (НМК). Цель: оценить влияние комбинированного введения агониста GPR119 с метформином и цитиколином на выраженность психоневрологических нарушений у животных с НМК на фоне СД. Методика. Исследование проведено на крысах линии Wistar, которым моделировали фокальную ишемию ГМ на фоне 28 дневного стрептозотоцин-никотинамид-индуцированного СД. Агонист рецептора GPR119 (дипиарон) и его комбинацию с метформином вводили с первого дня развития СД, а цитиколин - после моделирования НМК. Психоневрологические нарушения оценивались с использованием шкал «Combs & D’Alecy» и «Garcia», и тестов «Открытое поле», «Ротарод», УРПИ и ТЭИ. Результаты и обсуждение. Введение метформина приводило к нормализации уровня гликемии, но не снижало выраженность неврологического дефицита при последующем моделировании НМК. По сравнению с контролем в группах, получавших дипиарон и в большей степени его комбинацию с метформином, помимо улучшения контроля гликемии наблюдалось значительное снижение объема инфаркта и отёка мозга, а также выраженности психоневрологических нарушений у выживших животных (p<0,05). Введение цитиколина без гипогликемической терапии не приводило к снижению уровня неврологического дефицита по сравнению с контрольной группой, при этом добавление цитиколина к гипогликемической терапии значимо не снижало тяжесть течения НМК. Заключение. Комбинированное введение агониста GPR119 и метформина животным с экспериментальной ишемией ГМ на фоне СД значительно повышает терапевтический потенциал обоих препаратов, обеспечивая лучший контроль уровня гликемии и снижая выраженность психоневрологического дефицита при моделировании НМК. Type 2 diabetes mellitus (DM2) significantly increases the risk of stroke, and the choice of hypoglycemic therapy may influence not only a probability of stroke but also severity of cerebrovascular disease. Objective: To evaluate the effect of combination treatment with a GPR119 agonist, metformin and citicoline on severity of neurological disorders in animals with stroke and diabetes. Cerebral ischemia was modeled by intraluminal occlusion of the middle cerebral artery (OMCA). Methods. The study was performed on Wistar rats with 28-day streptozotocin-nicotinamide-induced diabetes. The GPR119 receptor agonist (dipiaron) and its combination with metformin were administered starting from the first day of DM, and citicoline was administered after the induction of brain ischemia. Behavioral and neurological disorders were evaluated using the Combs & D’Alecy and Garcia scales, and the open field, Rotarod, and active and passive avoidance tests. Results. The metformin treatment normalized glycemia but did not alleviate severity of the neurological deficit induced by subsequent OMCA. The groups treated with dipiaron and its combination with metformin, in addition to improved glycemic control, showed significant decreases in brain infarction volume and edema and the severity of neurological disorders in surviving animals compared to the control (p<0.05). Administration of citicoline without the hypoglycemic therapy reduced the neurological deficit in comparison with the control group. Addition of citicoline to the hypoglycemic therapy did not significantly reduce the severity of brain ischemia. Conclusion. The combination treatment of animals with brain ischemia and diabetes with the GPR119 agonist and metformin significantly enhanced the therapeutic potential of both drugs evident as a better glycemic control and alleviated severity of the neurological deficit following OMCA.

При моделировании депрессии у крыс в возрасте 12 месяцев изучены структурные изменения в гранулярном слое зубчатой извилины, установлена возможность фармакологической коррекции выявленных изменений фенибутом и соединениями с лабораторными шифрами ргПУ-189 (салифен -аддукт γ-амино-β-фенилмасляной и салициловой кислот), ргПУ-135 (нейроглутамβ-фенильное производное глутаминовой кислоты).Были сформированы 5 групп по 10 животных в каждой: контрольные крысы; крысы, подвергавшиеся ежедневно в течение 7 суток 30-минутному стрессированию; стрессированные крысы, получавшие фенибут, ргПУ-189, ргПУ-135.Депрессивноподобное состояние вызывали путем моделирования мягкого стрессового воздействия в специальной установке, позволяющей производить комбинирование нескольких стрессорных раздражителей (пульсирующий свет, громкий звук, вибрация).Показано, что после стрессового воздействия у животных в гранулярном слое зубчатой извилины наблюдалось увеличение удельного количества гиперхромных нейронов и удельного количества сморщенных гиперхромных нейронов.Применение соединения ргПУ-189 в большей степени оказывало корректирующее действие, поскольку способствовало снижению как обратимых, так и необратимых изменений в

The success of developing new drugs largely depends on the methodology of preclinical research. For developing cerebroprotective drugs, there are many experimental models with different complexity. In this review the most used stroke models are described and characterized, model procedures briefly described, own research experience in utilizing some model methods in establishing efficacy of drugs is also described.

Цель исследования — оценка влияния эндотелиальной дисфункции, вызванной снижением уровня эстрогенов после экстирпации матки на течение ишемии головного мозга. Методы. Эндотелиальная дисфункция вызывалась экстирпацией матки с придатками и подтверждалась подсчетом циркулирующих эндотелиальных клеток и оценкой стимулированной и базальной секреции оксида азота. Фокальная ишемия головного мозга моделировалась интравазальной окклюзией средней мозговой артерии. Тяжесть ишемии оценивалась по шкалам неврологического дефицита (Combs & D’Alecy и McGraw), в тесте Ротарод и по объему некроза. Результаты. Моделирование недостаточности половых гормонов у самок через 28 дней привело к повышению содержания циркулирующих эндотелиальных клеток на 88 %, а также снижению стимулированной и базальной секреции оксида азота соответственно на 17,1 и 14,7 % относительно группы ложно оперированных животных. Моделирование фокальной ишемии головного мозга у животных с эндотелиальной дисфункцией, вызванной недостаточностью половых гормонов, приводило к значительным повреждениям центральной нервной системы, что выражалось в повышении уровня неврологического дефицита по шкалам Combs & D’Alecy и McGraw в течение 7 дней, снижению времени удержания на вращающемся стержне на 32 %, а также увеличению зоны некроза головного мозга на 89 % относительно группы животных без недостаточности половых гормонов. Заключение. Показано, что эндотелиальная дисфункция, обусловленная моделированием недостаточности половых гормонов, осложняет течение ишемии головного мозга, вызывая более выраженный неврологический и моторный дефицит, и способствует увеличению размера некроза мозговой ткани.

BACKGROUND: Metabolic syndrome and obesity are often precursors of type 2 diabetes mellitus (DM), and current recommendations indicate the advisability of early initiation of drug therapy at the stage of prediabetes. Drugs with incretin activity are one of the priority groups for monotherapy of type 2 diabetes in the onset of the disease, and certain drugs are used to treat obesity. GPR119 agonists increase the secretion of endogenous incretins, and their effectiveness in the treatment of type 2 diabetes and obesity in mono- and combination therapy is currently being actively studied. AIM. To evaluate of the effect of administration of a GPR119 receptor agonist, its combination with metformin or sitagliptin on body weight, food intake and glycemia in rats under a high-calorie diet. MATERIALS AND METHODS: The study was conducted on 56 outbred female rats aged 78 months and an initial weight of 305320 g. Compound ZB-16 is a highly active GPR119 receptor agonist (EC50 = 7 nM). For 12 weeks, the animals were kept on a high-fat and carbohydrate diet and at the same time received the compound ZB-16, metformin and sitagliptin, or its combination (ZB-16 + metformin and ZB-16 + sitagliptin). During the experiment, the weight of the animals, the mass of feed eaten, as well as the level of glycemia after 6 hours of fasting and with an oral glucose load were assessed. RESULTS: In animals of the control group that were on a high-calorie and fatty diet for 12 weeks, an increase in body weight, glycemia and a decrease in the rate of glucose utilization were observed. The introduction of the GPR119 agonist (ZB-16) for 12 weeks led to a significant reduction in the amount of food consumed, limited weight gain and prevented the development of carbohydrate metabolism disorders. The addition of sitagliptin and especially metformin to therapy with the GPR119 agonist significantly increased the effectiveness of therapy compared to the control group, which was expressed in the normalization of animal body weight and glycemia (p 0.05). CONCLUSIONS: The introduction of a combination of the GPR119 agonist (compound ZB-16) with metformin and sitagliptin is more effective than monotherapy in terms of weight gain, food intake, and also prevents the development of carbohydrate metabolism disorders in animals when kept on a high-fat and carbohydrate diet.

The aim of this study was to assess the effect of endothelial dysfunction caused by a decrease in the estrogen level on the severity of cerebral ischemia. Methods. Endothelial dysfunction was caused by extirpation of the uterus with appendages and was confirmed by counting circulating endothelial cells and evaluating stimulated and basal secretion of nitric oxide. Focal cerebral ischemia was modeled by intravasal occlusion of the middle cerebral artery. The severity of ischemia was assessed according to the scales of neurological deficit (Combs & D’Alecy and McGraw), in the Rotarod test and in terms of the volume of necrosis. Results. Estrogen deficiency resulted in an increase in the circulating endothelial cells by 88%, as well as a decrease in stimulated and basal nitric oxide secretion by 17.1% and 14.7% respectively. Focal cerebral ischemia in animals with endothelial dysfunction caused by estrogen deficiency resulted in greater cerebral damage, resulting in an increase in the level of neurological deficit on the Combs & D’Alecy and McGraw scales for 7 days, a decrease in the retention time on the rotating rod by 32%, as well as an increase in the infarct volume by 89% relative to the group of animals without sexual hormones failure. Conclusion. It has been shown that endothelial dysfunction caused by estrogen deficiency complicates the severity of cerebral ischemia, causing a more pronounced neurological and motor deficit, and contributes to an increase in the size of infarct volume.

3,4,5-Trimethoxy- and 2-, 3-, and 4-acetoxybenzoylglycylglycines and their water-soluble potassium and lithium salts were synthesized. The cerebroprotective properties of the water-soluble potassium and lithium salts of acetoxybenzoylglycylglycines were studied experimentally. The most marked cerebroprotective proteins in cerebral ischemia were found with the lithium salt of 2-acetoxybenzoylglycylglycine.

Structural changes in hippocampal fields CA1 and CA3 of the ventral part of the hippocampus were studied in 12- and 24-month-old rats (n = 20). Paraffin sections of brains were stained by the Nissl method and the proportion of shrunken neurons with cytoplasmic hyperchromatosis was determined, along with changes in the expression levels of inducible and endothelial NO synthase (iNOS, eNOS). Older rats (24 months) showed more severe signs of neuron damage in the pyramidal layer of hippocampal field CA3. An increase in the proportion of shrunken neurons with cytoplasmic hyperchromatosis was seen, with a decrease in the relative density of neurons, accompanied by pericellular edema, and cytoplasmic vacuolization. An increase in iNOS expression in neurons in the pyramidal layer of field CA3 occurred, with decreases in eNOS expression in fields CA1 and CA3 both in neurons and in vascular endotheliocytes of the microcirculatory bed, as compared with levels in 12-month-old animals.