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.

No abstract

Chronic administration of 50% ethanol in a dose of 8 g/kg produces a toxic effect on functional activity of cardiomyocyte mitochondria, which manifested in decreased rates of respiration and oxidative phosphorylation. Structural GABA analogue Citrocard (phenibut citrate) and reference preparation piracetam in doses of 50 and 200 mg/kg, respectively, prevented the damaging effect of alcohol, which was seen from increased indexes of oxidative phosphorylation in treated animals compared to the control group.

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.

Substitution of drinking water for 1.8% NaCl in pregnant rats caused a pronounced increase in arterial pressure by 24,3% and urinary protein by 117% to day 21 of pregnancy. State 4 respiration of isolated placental mitochondria in the group of negative control was 3- and 1.5-fold higher with malate/glutamate and succinate as substrates than in placental mitochondria isolated from uncomplicated pregnant animals. This led to a decrease of the respiratory control ratio. These results suggest that development of experimental preeclampsia is accompanied by mitochondrial dysfunction through uncoupling of oxidative phosphorylation. Daily administration of sulodexide to females with experimental preeclampsia (EP) per os at a dose of 30 LE during the whole period of gestation decreased manifestations of the disease as evidenced by a slight increase in blood pressure (by 8,6%) and less pronounces increase in urinary protein (by 58,9%). Sulodexide decreased development of mitochondrial dysfunction in EP rats as shown a decrease of non-stimulated ADP respiration with malate/glutamate and succinate (4.5- and 2.5-fold, respectively) as compared with the negative control group and the corresponding increase in the respiratory control ratio (2.5- and 1.5-fold, respectively). Thus, sulodexide reduces uncoupling of oxidative phosphorylation and enhances the functional activity of mitochondria in EP animals, possibly due to its antioxidant and endotelioprotective effects.

Objectives The objective of this study was to investigate the effects of a new derivative of GABA, RGPU-207 compound, on the mitochondrial functions of stressed animals. Methods RGPU-207 and the comparator drugs (phenibut and piracetam) were administered intraperitoneally to unstressed and stressed male rats at a dose of 9.4, 25 and 400 mg/kg, respectively. The oxygen consumption by cardiac and cerebral mitochondria in state 3 and 4 and Chance's respiratory control ratio (RCR) was investigated. The concentration of lipid peroxidation products (LPO) such as malondialdehyde (MDA), conjugated dienes (CD) and diketones was evaluated in the isolated mitochondria, as well as the activity of the antioxidant system (AOS) enzymes (superoxide dismutase (SOD), glutathione peroxidase (GP) and catalase). Key findings A new cyclic GABA derivative, RGPU-207 compound, at the dose of 9.4 mg/kg promotes a decline in MDA, diketone and CD concentrations in mitochondria and increases the levels of SOD, GP and catalase activity. Mitochondrial functional activity increases: oxygen consumption by cerebral mitochondria in state 4 decreases when complex I of the respiratory chain is activated, while malate-dependent state 3 respiration of cardiac mitochondria tends to increase. RCR of cardiac mitochondria increases when complexes I and II are involved. In cerebral mitochondria, malate-dependent and succinate-dependent RCR rise. Conclusions Twenty-four-hour immobilization and pain stress activate LPO processes inhibit the activity of the aos enzymes and decrease the functional activity of cardiac and cerebral mitochondria. RGPU-207 restricts LPO, enhances the antioxidant enzyme activity and improves the mitochondrial respiration. The efficacy of RGPU-207 is comparable with phenibut and piracetam.

No abstract

No abstract