[Synergistic effects of GABA and hypoglycemic drugs].

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 «old¼ 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 ß-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 ß-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 ß-cells, increases ß-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 ß-cells, an increase in ß-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 role of iNOS inhibition in the mechanism of the cardioprotective effect of new GABA and glutamic acid derivatives in the model of acute alcoholic myocardial injury in rats.

The cardioprotective effects of new derivatives of glutamic acid (glufimet) and GABA (mefargin) were studied in rats exposed to acute alcohol intoxication (AAI) under conditions of selective blockade of inducible NO-synthase (iNOS). AAI induced a pronounced decrease in the contractile function of the myocardium during exercise tests (load by volume, test for adrenoreactivity, isometric exercise), caused mitochondrial dysfunction and increased processes of lipid peroxidation (LPO) in heart cells. A decrease in NO production during iNOS inhibition and AAI improved the respiratory function of mitochondria, a decreased the level of LPO products, and increased mitochondrial superoxide dismutase activity of heart cells. This led to an increase in myocardial contractility. The studied compounds, glufimet and mefargin, caused a statistically significant increase in the rates of myocardial contraction and relaxation, left ventricular pressure, and also reduced NO production. This was accompanied by a decrease in the intensity of LPO processes and an increase in the respiratory control ratio (RCR), reflecting the coupling between respiration and phosphorylation processes during activation of the respiratory chain complexes I and II. The decrease in NO concentration during selective blockade of iNOS and administration of the studied substances was less pronounced than without blockade of the enzyme. This suggests the putative effect of new derivatives of neuroactive amino acids on the NO system.

[Changes in the psychoemotional state under the influence of derivatives of neuroactive amino acids of rats after chronic alcohol intoxication]. / Izmenenie psikhoemotsional'nogo sostoyaniya pod vliyaniem proizvodnykh neiroaktivnykh aminokislot u krys posle khronicheskoi alkogol'noi intoksikatsii.

OBJECTIVE: To study an effect of neuroactive amino acids derivatives glufimet and mefargin on the psychoemotional state of rats after chronic alcohol intoxication (CAI). MATERIAL AND METHODS: The study was carried out on 10-month-old female Wistar rats. CAI was modeled by replacing drinking water with a 10% solution of ethyl alcohol sweetened with sucrose (50 g/l) for 6 months. Animals (age - 16 months) were divided into groups at the end of alcoholization: 1 (n=15) - intact group - rats without CAI; 2 (n=14) - control - females after CAI; 3 (n=11), 4 (n=14), 5 (n=11) and 6 (n=10) - experimental - females after CAI who received the GABA derivative mefargin (25 mg/kg), the glutamic acid derivative glufimet (29 mg/kg) and comparison drugs phenotropil (25 mg/kg) and heptral (100 mg/kg), respectively. Substances were administered to rats after 6 months of alcoholization intraperitoneally once a day for 14 days, the intact and control groups received physiological saline. The psychoemotional state of the animals was studied in the «Open field¼ test, «Elevated plus maze¼ test, «Marble burying¼ test and the Porsolt swim test after the treatment. RESULTS: In animals of the control group, an increase in anxiety was noted, as evidenced by a greater number of boluses in the Open Field test (3.43±0.56 vs. 1.47±0.39) compared to the intact group (p<0.05), short duration of stay in open arms (26.07±3.47 vs. 68.67±10.08) and fewer hangings from them (3.07±0.25 vs. 6.67±0.79) in the «Elevated plus maze¼ test. Rats after CAI buried more balls (8.79±1.15 versus 2.73±0.71, p<0.05), which indicated that they had compulsive behavior. In addition, females of the control group were observed to be depressed, as evidenced by a long period of immobilization in the Porsolt swim test (2.36±0.41 versus 0.87±0.31, p<0.05). CONCLUSION: Mefargin, glufimet, phenotropil and heptral restricted anxiety and manifestations of obsessive-compulsive disorder in females subjected to alcoholism (p<0.05). The antidepressant effect was observed in animals treated with phenotropil and heptral after CAI (p<0.05).

[Antioxidant effect of cortexin, cerebrolysin and actovegin in rats with chronic cerebrovascular insufficiency]. / Antioksidantnoe deistvie Korteksina, Tserebrolizina i Aktovegina u zhivotnykh s khronicheskoi ishemiei golovnogo mozga.

OBJECTIVE: To compare the antioxidant effects of cortexin, cerebrolysin and actovegin in rats with chronic brain ischemia. MATERIAL AND METHODS: Chronic brain ischemia was modeled in male rats by 50% stenosis of the common carotid arteries. Forty days after surgery, the animals received 2 ten-day courses of therapy, separated by a break of 10 days. Placebo, cortexin (0.3, 1 and 3 mg/kg), cerebrolysin (0.8, 2.5 and 7.5 ml/kg) and actovegin (5 ml/kg) were administered to animals as treatment. The concentration of malondialdehyde (MDA) in the homogenates was determined by the reaction with thiobarbituric acid, the concentration of reduced glutathione was determined by the reduction reaction of 5.5-dithiobis- (2-nitrobenzoic acid); determination of catalase activity, as well as the content of lactate and pyruvate, by commercially available reagent kits. The activity of superoxide dismutase (SOD) was determined by the photometric method based on an assessment of the degree of inhibition of the epinephrine oxidation reaction. All reactions were carried out in triplicates. RESULTS: Modeling of chronic brain ischemia led to the statistically significant decrease in the content of lactate and pyruvate (p<0.001, when compared with the control group), which was not accompanied by a significant decrease in their ratio (p>0.05), as well as to the decrease in SOD, catalase activity, restored glutathione and increase in MDA concentrations. Compared with the control group, in the groups that received cortexin at a dose of 3 mg/kg/day, cerebrolysin at a dose of 7.5 ml/kg/day and actovegin at a dose of 5 ml/kg/day, there were an increase in the content of lactate and pyruvate (without a significant change in their ratio), restoration of glutathione levels and the activity of SOD and, to a lesser extent, catalase, combined with a decrease in the concentration of MDA. CONCLUSION: Course administration of cortexin (3 mg/kg), cerebrolysin (7.5 ml/kg) and, to a lesser extent, actovegin (5 ml/kg) has a positive effect on the state of the antioxidant system of the brain in rats with chronic brain ischemia.

Effect of RGPU-260, a Novel GABA Derivative, on Functional Reserves of Rat Heart after Chronic Alcohol Intoxication.

The effect of a new derivative of GABA, the compound RGPU-260, on the heart contractility of rats exposed to chronic alcohol intoxication (10% ethanol solution for 24 weeks) was studied. In comparison with intact rats, the alcoholized ones were characterized with smaller increments in the rates of myocardial contraction (+dP/dtmax) and relaxation (-dP/dtmax), left ventricular pressure, and maximum intensity of functioning of structures during the load tests (volume load/preload, stimulation of the cardiac adrenergic receptors, and occlusion of the ascending aorta/afterload) attesting to degraded cardiac contractility function. In rats treated with RGPU-260 (daily, 25 mg/kg intragastrically during 14 days), these parameters were higher in comparison with control values indicating a positive action of the examined agent on inotropic function of the heart. Effectiveness of cardiotropic action of RGPU-260 was comparable to that of the reference drug mildronate.

Peculiarities of the Expression of Inducible NO Synthase in Rat Dentate Gyrus in Depression Modeling.

Mild stress exposure contributes to the development of cognitive and emotional deficits, is considered as a model of depressive state, and is characterized by enhanced NO production. In albino mature (12-month-old) male rats, the depressive state was simulated by daily 30-min exposure to stressful stimuli (vibration, loud sound, and strobe light) over 7 days in a special chamber. On paraffin frontal sections of the brain stained with antibodies against inducible NO synthase (iNOS), the expression and distribution pattern of immunoreactive material were evaluated in various layers of the dentate gyrus under normal conditions and after depression modeling. The relative area of iNOS expression in the dentate gyrus of control rats was 8.2 (7.1-9.9)%, while in rats with experimental depression, this parameter was 16.7 (10.5-22.1)%, i.e. increased by 8.5% (p<0.05). In mature rats with modeled depressive state, the expression and relative area of iNOS expression in neuronal perikarya in the granular and subgranular layers of the dentate gyrus increased, which can underlie the mechanisms of damage and determine reduced neuroplasticity and suppressed neurogenesis in the dentate gyrus in rats during adulthood.

[Comparative study of protective effects of Cortexin, Cerebrolysin and Actovegin on memory impairment, cerebral circulation and morphological changes in the hippocampus of rats with chronic brain ischemia]. / Sravnitel'noe izuchenie vliyaniya Korteksina, Tserebrolizina i Aktovegina na sostoyanie pamyati, mozgovoe krovoobrashchenie i strukturu gippokampa u krys s khronicheskim narusheniem mozgovogo krovoobrashcheniya.

OBJECTIVE: To compare the effects of cortexin, cerebrolysin and actovegin on memory impairment, cerebral circulation and morphological changes in the hippocampus of rats with chronic brain ischemia. MATERIAL AND METHODS: The study was conducted using male rats with chronic brain ischemia caused by stenosis of the common carotid arteries by 50%. Animals received cortexin (0,3; 1 or 3 mg/kg), cerebrolysin (0,8; 2,5 or 7,5 ml/kg) and actovegin (5 ml/kg) in two 10-day courses with 10 days of treatment break. The severity of cognitive impairment was evaluated using the Morris water maze, passive and active avoidance tests. Cerebral circulation using laser flowmetry and brain hippocampus structures were studied in the end of treatment. RESULTS: Cognitive impairment in animals with chronic brain ischemia was accompanied by the development of pathological changes in the CA1 and CA4 regions of the hippocampus. Administration of cortexin (1 and 3 mg/kg) and cerebrolysin (2.5 and 7.5 ml/kg) to rats with chronic brain ischemia had almost no effect on cerebral blood flow, but contributed to the improvement in memory formation and retrieval processes in the Morris water maze. The treatment effect was comparable for both drugs and persisted after 10 days of treatment break. Morphological assessment showed a decrease in the severity of pathological changes in the hippocampal regions. CONCLUSION: The course-administration of cortexin and cerebrolysin lead to a decrease in the severity of memory impairment and pathomorphological changes in the hippocampus in rats with chronic brain ischemia.

Correction of Alcohol-Induced Damage to Mitochondria in Cardiac and Cerebral Cells by Derivatives of Neuroactive Amino Acids.

We studied LPO intensity and respiration of mitochondria in brain and heart cells of rats receiving 5% ethanol for 20 weeks and treated with derivatives of neuroactive amino acids. Chronic semicompulsory alcohol intoxication increased the concentration of LPO products in cardiac and cerebral mitochondria by 46 and 45% (diene conjugates), by 97 and 8% (diketones), and by 28 and 81% (malondialdehyde), respectively, reduced activity of antioxidant enzymes in cardiac and cerebral mitochondria by 24 and 45% (glutathione peroxidase) and by 22 and 26% (superoxide dismutase), respectively, and uncoupled the process of respiration and ATP synthesis, which manifested in a decrease in respiratory control (V3/V4 ratio according to Chance). Glutamic acid derivative Neuroglutam (26 mg/kg) and GABA derivative succicard (44 mg/kg) administered intraperitoneally daily for 28 days after termination of alcoholization decreased the levels of primary and secondary LPO products, up-regulated activity of antioxidant enzymes in mitochondria of the heart and brain, and moderated the mitochondrial dysfunction.

Effects of Gaba Derivatives on Anxious and Compulsive Behavior in Offspring of Rats with Experimental Preeclampsia.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

[Age-specific changes in the functional indices of rats' cardiac mitochondria in chronic alcohol intoxication.]

The effect of chromic continuous consumption of 5 and 10% ethyl alcohol over 6 months on the respiratory function and oxidant/antioxidant status of rats' cardiac mitochondria of different gender and age has been studied. A decrease in oxygen consumption rate by cardiomyocyte mitochondria in the metabolic conditions V2, V3, V4 according to Chance involving activation of respiratory chain complexes I, I+II and II in elderly (24-month old) animals as compared to young (11-month old) animals. As the rats were ageing, the concentration of lipid peroxidation (LPO) products (malondialdehyde) was increasing, while the activity of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) was decreasing in cardiomyocyte mitochondria. Chronic alcoholization of 24-month old rats of both genders resulted in a more pronounced decline in the respiratory function activity of cardiac mitochondria, uncoupling of respiration and oxidative phosporylation, reduced activity of antiradical protection enzymes and increased LPO products as compared to younger rats.

Composition and cardioprotective effects of Primula veris L. solid herbal extract in experimental chronic heart failure.

BACKGROUND: High interest in chronic heart failure (CHF) is accounted for by its high incidence, poor prognosis, growing number of hospital admissions due to the heart failure relapse, and inadequate treatment. These facts necessitate a search for new pharmacological agents for the CHF correction. Herbal medicinal products appear to be very promising as they have a noticeable therapeutic effect and tend to be more harmless in comparison to the most of synthesized medications. PURPOSE: Our aim was to study the composition of the Primula veris L. solid herbal extract (PVSHE) and its effects on the myocardial contractile function in animals with experimental CHF. STUDY DESIGN: The study design involved the identification of the raw material composition of the P. veris L. extract. For the experimental part of our research, we used the model of CHF to elucidate the cardioprotective properties of PVSHE. METHODS: The active extract constituents were isolated by thin-layer chromatography and column chromatography; the extract components were identified by high-performance liquid chromatography, ultraviolet spectroscopy (UVS), and nuclear magnetic resonance spectroscopy (NMRS). To model CHF, L-isoproterenol at a dose of 2.5 mg/kg was intraperitoneally injected to the experimental rats twice a day for 21 days. Cardiac output was assessed with the loading test, adrenoreactivity test, and maximum isometric loading test; CHF markers adrenomedullin and copeptin were detected in blood plasma with ELISA kit for adrenomedullin and copeptin (Coud-Clone Corp., USA). RESULTS: P. veris L. solid herbal extract contains flavonoid aglycons (apigenin, quercetine, kaemferol), flavonoid glycosides (cinarozid, rutin, hyperozid), as well as polymethoxylated flavonoids acting as chemotaxonomic markers for the genus Primula (8-methoxy-flavone; 3',4'methylenedioxy-5'-methoxyflavone). The substance 3',4'methylenedioxy-5'-methoxyflavone has been isolated from the primrose herb for the first time. We showed that the PVSHE has a cardioprotective effect when it was administered at a dose of 30 mg/kg in the experimental CHF, as evidenced by a lower number of animal death, lower level of CHF markers in the blood plasma of the experimental animals, the higher increase in rate of myocardial contraction and relaxation, the higher level of left ventricular pressure (LVP) and of maximum intensity of structural performance (MISP), as compared to the control group. CONCLUSION: P. veris L. solid herbal extract contains flavonoid aglycons, flavonoid glycosides, and polymethoxylated flavonoids. The herbal agent increases the myocardial contractility in experimental CHF.

[Influence of the dense extract from herb of Primula veris L. On the oxidative stress development and the functional state of the cardiomyocytes mitochondria of rats with experimental chronic heart failure]. / Vliianie gustogo ékstrakta iz travy pervotsveta vesennego na razvitie oksidativnogo stressa i funktsional'noe sostoianie mitokhondrii kardiomiotsitov krys s éksperimental'noi khronicheskoi serdechnoi nedostatochnost'iu.

Experimental chronic heart failure (CHF), caused by administration of L-isoproterenol (2.5 mg/kg twice a day intraperitoneally for 21 days), promotes uncoupling of respiration and oxidative phosphorylation. The rate of mitochondrial oxygen consumption in the metabolic state V3 by Chance in animals with CHF decreased by 53.3% (p<0.05) with malate using (as an oxidation substrate feeding сomplex I of the electron transport chain (ETC)), by 70.6% (p<0.05) with succinate using (сomplex II substrate) and by 63.6% (p<0.05) when malate and succinate were added simultaneously. The respiratory control ratio significantly decreased 2.3 times for сomplex I, 2.5 for сomplex II, and 2.6 times for the simultaneous operation of two respiratory chain complexes in mitochondria of CHF rats compared to intact animals. Mitochondrial dysfunction in experimental CHF is evidently due to the development of oxidative stress. It was revealed that the content of malonic dialdehyde (MDA) in the group of rats with experimental CHF was higher by 54.7% (p<0.05), as compared with intact animals. The activity of superoxide dismutase (SOD) and catalase was lower by 17.5% (p<0.05), and by 18.4%, respectively than in the intact group. The dense extract from herba of Primula veris L. (DEHPV) 30 mg/kg limits the development of mitochondrial dysfunction in rats with experimental CHF, as evidenced by an increase in the role of V3 respiration for the first and second respiratory chain complexes in 1.7 (p<0.05) and 2.0 times (p<0.05), respectively, the ratio of respiratory control (RCR) - 1.7 times (p<0.05) for сomplex I and 2 times (p<0.05) for сomplex II compared with the negative control. The concentration of MDA was by 15.7% (p<0.05), lower and the activity of SOD was by 56.3% (p<0.05) higher.

Expression of Beclin-1 and LAMP-2 in Rat Hippocampus under Conditions of Simulated Gravity Overload in the Caudocranial Vector.

Structural changes in the rat hippocampus in response to chronic cerebrovascular disorders induced by gravity exposure in the caudocranial vector were studied. Qualitative and quantitative morphological analysis detected significant cytoarchitectonic changes in the pyramidal layer: spongiosis, manifest pericellular and perivascular edema, and a drastic increase in the counts of pyramidal neurons with signs of impairment in all hippocampal zones. The density of perikarya in the pyramidal layer decreased. Immunohistochemical study detected high expression of Beclin-1 in CA1 field. High expression of LAMP-2 was detected in CA4 field. Field CA2 was characterized by the maximum counts of damaged cells and high expression of Beclin-1 and LAMP-2.

Evaluation of DNA Damage in Experimental Preeclampsia by Comet Assay.

Experimental preeclampsia induced by substitution of drinking water with 1.8% NaCl during pregnancy was associated with an increase in the level of DNA damage in fetal brain and placenta measured by DNA comet assay by 35.7 and 27.8 times, respectively, in comparison with physiological pregnancy.

Inhibition of the Expression of Inducible NO Synthase by Neuroactive Amino Acid Derivatives Phenibut and Glufimet In Vitro and Ex Vivo.

The effects of glufimet and phenibut (glutamic acid and GABA derivatives, respectively) on concentration of inducible NO synthase and cGMP in LPS-activated mouse peritoneal macrophages and on NO end products in their culture medium were examined in vitro and ex vivo. Addition of LPS into culture medium elevated concentration of NO metabolites in this medium and increased concentration of inducible NO synthase and cGMP in the lysates of peritoneal macrophages, whereas incubation of the cells with examined agents applied at concentration of 10-5 M diminished these indices. Similar results were obtained with intraperitoneal injection of LPS, glufimet, and phenibut. In culture medium containing peritoneal macrophages from the mice injected with LPS (100 µg/kg), the concentrations of inducible NO synthase and cGMP as well as the total concentration of nitrite and nitrate ions increased, whereas in culture medium with the cells from LPS-exposed mice treated with glufimet (28.7 mg/kg) and phenibut (50 mg/kg) these indices significantly decreased.

[Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction]. / Fokal'naia ishemiia golovnogo mozga u krys na fone nedostatochnosti éstrogenov i éndotelial'noi disfunktsii.

AIM: To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. MATERIAL AND METHODS: The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. RESULTS AND CONCLUSION: After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

[Behavioral phenotyping in rats during the experimental modeling of chronic cerebral circulation disorder]. / Povedencheskoe fenotipirovanie krys pri éksperimental'nom modelirovanii khronicheskogo narusheniia mozgovogo krovoobrashcheniia.

AIM: To describe motor, adaptive and cognitive disorders in rats with chronic cerebral circulatory deficiency caused by partial stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: A study was performed on 20 white outbred male rats. This manipulation led to 40-45% and 50-60% reduction of blood flow in CCA and in the brain, respectively. Twenty days after operation, animal's condition was assessed in the following tests: open field test, rotarod performance test, marble burying test and novel object recognition. RESULTS AND CONCLUSION: After 20 days of experimental CCA stenosis, animals demonstrated several signs of neuropsychiatric deficiency including coordination disorders, a decrease in locomotor activity as well as in explorative and protective behavior. The model of CCA partial stenosis could be used during further studies of the pathophysiology and pharmacology of chronic cerebral circulatory deficiency.

Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade.

Increased oxygen consumption by heart and brain mitochondria in the absence of ADP and reduced mitochondrial respiration in the presence of ADP were observed in rats exposed to stress simulated by suspension by the dorsal neck skin fold for 24 h, which attests to uncoupling of substrate oxidation and ATP synthesis and can cause electron drain from the respiratory chain, formation of ROS, and oxidative damage to cell structures. Blockade of inducible NO synthase with aminoguanidine (single intraperitoneal dose of 50 mg/kg before stress exposure) increased coupling of respiration and oxidative phosphorylation in heart and brain mitochondria of rats exposed to immobilization-painful stress, which was especially pronounced in cardiomyocytes. The test compounds glufimet (single intraperitoneal dose of 29 mg/kg before stress exposure) and phenibut (single intraperitoneal dose of 50 mg/kg before stress exposure) limited stress-induced mitochondrial damage against the background of inducible NO synthase blockade and without it, which was seen from increased respiratory control ratio in comparison with that in untreated rats exposed to stress (control).

[Protective effects of a new glutamic acid derivative against stress after nNOS blockade]. / Stressprotektornoe deistvie novogo proizvodnogo glutaminovoi kisloty pri blokade neironal'noi NO-sintazy.

We studied the effects of a new glutamic acid derivative, glufimet, on oxidative stress, activity of antioxidant enzymes, mitochondrial respiration, endothelial vasodilation and anti-platelet activity in female rats after exposure to 24-hour immobilization pain stress and 7-nitroindazole, a neuronal nitric oxide synthase (nNOS) inhibitor. A single dose administration of glufimet (29 mg/kg intraperitoneally) 10 minutes before stress exposure caused a decrease of NO metabolites in serum (by 27.2%) and heart homogenate (33.5% (p£0.05), respectively, compared with the control group. Administration of 7-nitroindazole with glufimet also decreased the studied parameters by 14.3% in the heart homogenate and by 30,3% in the brain (p£0.05) compared with stress exposed rats receiving only the nNOS inhibitor. Glufimet decreased the levels of primary and secondary products of lipid peroxidation (LPO), conjugated dienes by 20% (p£0.05) and 17.3% (p£0.05), ketodienes by 16% and 13.7%, malondialdehyde by 15% (p£0.05) and 26.6% (p£0.05) in the heart and brain mitochondria of stress exposed rats, respectively, compared with the control group. Glufimet administration also increased SOD activity (by 14.4% and 13.1%, respectively), catalase (by 19% and 26.8%, respectively) and glutathione peroxidase (GPx) activity (by 45.5% (p£0.05) and 7.3%, respectively). The antioxidant effect of glufimet may be also attributed to increased coupling between the processes of mitochondria respiration and oxidative phosphorylation. This was evidenced by an increase in the respiratory control ratio (RCR) (by 46.0% (p£0.05) for malate/glutamate and by 49,7% (p£0.05) for succinate) in the heart mitochondria. A statistically significant increase in RCR (by 37.3% (p£0.05)) was observed in stress exposed female rat brain mitochondria for succinate. RCRs differed significantly for succinate in the heart and brain of rats receiving glufimet after nNOS blockade. RCR increased by 62.3% (p£0.05) in the heart mitochondria and by 72.2% (p£0.05) in the brain mitochondria compared with the RCRs in stress exposed rats receiving 7-nitroindazole.