Search

Objective: To evaluate an effect of ethylmethylhydroxypyridine succinate and ethylmethylhydroxypyridine malate on changes in mitochondrial function under experimental focal cerebral ischemia., Material and Methods: Focal cerebral ischemia was modeled in Wistar rats by thermocoagulation of the middle cerebral artery. Ethylmethylhydroxypyridine succinate («Mexidol») and ethylmethylhydroxypyridine malate («Ethoxidol») were injected into the tail vein 30 minutes after ischemia simulation and then for 3 days at doses of 50 mg/kg, 100 mg/kg and 150 mg/kg. After 72 hours, changes in neurological deficits, aerobic and anaerobic respiration activity, the concentration of mitochondrial hydrogen peroxide and apoptosis-inducing factor, as well as the activity of succinate dehydrogenase and cytochrome c oxidase in brain tissue supernatants were assessed., Results: The course administration of ethylmethylhydroxypyridine succinate and ethylmethylhydroxypyridine malate dose-dependently contributed to a decrease in the concentration of mitochondrial hydrogen peroxide and apoptosis-inducing factor in the brain tissue. The restoration of mitochondrial energy function was also shown with the use of ethylmethylhydroxypyridine succinate in all studied doses, while the administration of ethylmethylhydroxypyridine malate led to the restoration of mitochondrial-dependent energy production only at higher doses (100 mg/kg and 150 mg/kg)., Conclusion: The effect of malic acid and succinic acid salts of ethylmethylhydroxypyridine on the change in the redox and apoptosis-regulating function of mitochondria does not depend on the type of anion, whereas the change in the energy function of mitochondria is associated with the salt residue included in the drug structure and its dosage.

This work deals with study, of effect of yttrium acetate (Y3+) on myocardium of the frog Rana redibunda and of its action on the ion transport across the inner membrane of the rat heart mitochondria. It was found that Y3+ decreased strength of heart contractions and facilitated transport of ions in rat heart mitochondria stimulated by 10 mM glutamate and 2 mM malate. In the presence of Y3+, the energy-dependent transport of Ca2+ in mitochondria was inhibited; this was manifested as a decrease of their swelling in the medium containing 125 mM NH4NO3 and Ca2+ or 25 mM potassium acetate, 100 mM sucrose and Ca2+. It is assumed that the Y(3+)-caused decrease of the heart muscle contractility is not only due to its direct blocking effect on the potential-operated Ca2+ channels of the pacemaker and contractile cardiomyocytes, but also due to its mediated action on active transport of Ca2+ in mitochondria. The data that Y3+ activates transport of K+ via the mitochondrial potassium uniporter and blocks Ca(2+)-channels of the inner mitochondrial membrane are important for better understanding of mechanisms of action Y3+ on cardiomyocytes of vertebrate animals and humans and the possible use of Y3+ in medicine.

In order to create new oral vanadyl organic complexes-based drugs for the treatment of diabetes mellitus biligand vanadyl derivative of L-malic acid (bis(L-malato)oxovanadium(IV) was prepared and its potential as a novel hypoglycemic agent was studied in the streptozotocin-diabetic rats. We show that the oral administration of bis(L-malato)oxovanadium(IV) with drink water significantly reduced glucose concentration in blood and urine, as well as the level of glycated proteins in the streptozotocin-diabetic rats.

The effects of malate, succinate, and glutamate on the kinetics of changes in the pH gradient (delta pH) and membrane potential (delta psi) on the peribacteroid membrane (PBM) of the symbiosomes of bean root nodules varying in age were recorded spectrophotometrically. Addition of all the tested metabolites to potassium-free incubation medium stimulated a passive acidification of the peribacteroid space (PBS) and dissipation of delta psi in PBM of young developing nodules in the presence of the K+/H+ antiporter nigericin in the medium. However, in mature nodules with a high nitrogen-fixing activity, only malate and succinate (but not glutamate) increased delta pH during both passive and ATP-dependent PBS acidification. Dicarboxylates also caused dissipation of both delta pH in the presence of nigericin in the medium and delta psi generated on PBM by H+-ATPase. A decrease in the effects of metabolites on delta pH and the absent activity of the PBM H+ pump were observed in the aging nodules. The obtained data on the changes in deltapH and dlta psi caused by the metabolites in question suggest that PBM is permeable for all these metabolites only in young nodules. Only malate and succinate (but not glutamate) are transported through PBM in mature nodules; and the rate of metabolite translocation through PBM in aging nodules is decreased.

The purpose of this study was to examine hepatocyte mitochondrion respiratory chain in rats subjected to ethanol and CCl4 administration within 4 weeks to induce an experimental hepatitis. Oxygen consumption was determined as a measure of mitochondrion respiration chain function. The development of liver pathology was accompanied by fat accumulation, fibrosis, triglycerides and lipid peroxidation increase. Respiratory chain characteristics damage was found. Endogenous oxygen consumption by hepatocytes isolated from pathological liver was found 34% higher compared to control. Exogenous malate and pyruvate substrates delivery didn't stimulate cell respiration. Rotenone (the inhibitor of the I complex) decreased 27% oxygen consumption by pathological hepatocytes while dinitrophenol produced 37% cell respiration increase. States 3 (V3) and 4 (V4) mitochondrial respiration with malate + glutamate as substrates were found to be 70 and 56% higher accordingly compared to control level. V3 and Vd (dinitrophenol respiration) for mitochondria from pathological liver didn't differ from control when being tested with malate + glutamate or succinate as substrates. Cytochrome c oxidase activity increased (+ 80%) as compared to control. Administration of hypolipidemic agent simvastatin simultaneously with ethanol and CC14 resulted in decrease liver fat accumulation, fibrosis and peroxidation products. Simvastatin administration caused hepatocyte endogenous respiration decrease while malate + pyruvate, dinitrophenol or rotenone delivery produced oxygen consumption alterations similar to control. However, when isolated mitochondria from liver of simvastatin treated animals being tested the decrease of oxidative phosphorylation coupling for substrates malate + glutamate was found. While simvastatin did not cause changes in cytochrome c oxidase activity. We propose the hypothesis that the NCCR complex in rat mitochondria with experimental toxic hepatitis works extensively on superoxydanion production. Alterations of SCCR, Coenzyme Q-cytochrome c-reductase, cytochrome c oxidase and ATP-synthase activities have an adaptive nature to compensate for impaired NCCR function.

Mitochondrial substrate-based preparations corrected disorders, caused by long-term exposure to abnormal gravitation vector in head-down tilt (hanging) test in rats. The preparations produced systemic and polyorgan protective effects consisting in correction of the blood prooxidant/antioxidant balance, energy metabolism in musculus soleus, and minimization of morphological changes in the liver and kidneys.

The effect of malate on respiration in liver mitochondria has been studied during oxidation of succinate in the presence of rotenone both in state 3 and after palmitate addition. Malate was shown to stimulate the rate of mitochondrial respiration in the both respiratory states, its effect being increased in the presence of the NAD-dependent substrates of oxidation-glutamate and pyruvate or thiols (cysteine and thiourea) Preincubation of mitochondria for 5 min in the absence of respiratory substrates eliminated the stimulating effect of malate. However, this effect was manifested in the conditions when the NAD-dependent respiratory substrates or thiols were added after preincubation of mitochondria. p-Chloromercuribenzoate eliminated the stimulating effect of malate. Carboxyatractyloside and ATP inhibited mitochondrial respiration in the presence of palmitate. Malate did not influence the action of the first effector but eliminated that of the second effector. It is concluded that malate can regulate oxidative phosphorylation and palmitate-uncoupled respiration by affecting the adenine nucleotide transported. The SH-groups localized outside the mitochondria in the hydrophilic region play an important role in the realization of malate effects.

Influence of fructose++-1,6-diphosphate, succinate, malate and cytochrome C on free lipid peroxidation (FLP), infarct sizes and metabolic acidosis was studied in experiments on rats. The good correlation between inhibition of FLP and cardioprotector activity was established for activators of glycolytic energy production only. Krebs' cycle metabolites limited the zone of myocardial necrosis after coronary occlusion without any significant depression of FLP. Succinate and malate were practically inactive under acute metabolic acidosis of isolated rat heart.

Anti-ischemic action of exogenous natural metabolites and their effect on biological combustion processes indexes in cardiac muscle has been investigated on white rats with the experimental myocardial infarction. It has been established that the marked cardioprotective effect of malate and alpha-ketoglutarate is associated with the glycolysis and enzymes activation of creatine kinase system of energy transport. At the same time malate activates pentose-phosphate cycle and tissue respiration enzymes. alpha-glycerophosphate displays definite anti-ischemic properties not associated with the intervention into biological combustion processes.

Malate was studied for its effect on the oxidative phosphorylation rate in the rat brain mitochondria in the presence and absence of ATP, succinate being used as a substrate of the respiration. It has been found that malate in the 0.05-0.4 mM concentration range increases the oxidation phosphorylation rate. ATP inhibiting oxidative phosphorylation intensifies the malate stimulation. The malate 0.8 mM concentration removes the inhibiting action of ATP. The regulatory effects of malate and ATP are supposed to be realized at the adenine nucleotide translocator step.

Two phases were established in the synthesis of extracellular proteases by Bacillus mesentericus 73. When the growth rate was high, the synthesis of proteases was small. The maximum rate of the enzyme synthesis was observed when the growth decelerated and the production of spores started. The synthesis of alkaline protease and the formation of spores are susceptible to nitrogen-metabolite and catabolite repression. The ability to produce spores was not found in the S variant of Bacillus mesentericus that did not synthesize extracellular proteases.

The effect of malic acid salts of iron, potassium, copper, chromium, lithium and zinc on the motor activity and electroencephalographic indices in rats was studied under the course of oral treatment (250 mg/kg). Potassium malate was found to exert the most pronounced stimulating effect on the motor activity and excitatory processes in the sensory motor brain areas. The study of the influence of this compound on total physical working capacity and its restoration revealed a significant dose-dependent stimulating action. It was shown that the effects of potassium malate are related to its ability to stimulate the most productive bioenergetic processes, to increase carbohydrate reserves, to decrease oxygen consumption of tissues.

The submitochondrial particles (SMP, inverted inner membrane vesicles of mitochondria of the turned out vesicles in internal mitochondrial membranes) of the rat liver are characterized for their ability to incorporate [14C]citrate depending on the concentration of exogenic citrate, temperature and time of incubation. The rate of citrate incorporation into SMP does not depend on the addition of the oxidation substrate into the medium, however in the presence of malate and phosphate it is sharply activated. 1,2,3-benzene tricarboxylase (1,2,3-BTC) is an active inhibitor of the citrate transport into SMP. The citrate transport is determined by the protonation-deprotonation processes of the carrier protein on the outer and inner side of the membrane. A decrease in the pH of the medium favours protonation of the carrier protein on the outer side of the membrane and intensifies [14C]citrate incorporation into SMP, whereas the pH increase inhibits this process. The effect of pH changes is less pronounced in the presence of K+ ions. Valinomycin in the K+ medium activates incorporation of [14C]citrate increasing the carrier protein deprotonation rate on the inner side of the SMP membrane. Protonophore separators intensify conductivity for H+ ions and remove the stimulating influence of valinomycin on the rate of [14C]citrate incorporation into SMP.

In acute experiments on cats the effects of malate (100 mg/kg), NAD (0.2 mg/kg) and their combination on regional myocardial contractility were studied during acute coronary artery occlusion. All the drugs increased significantly myocardial contractility in border and intact zones. However, the response of the central ischemic zone to drug effects was insignificant.

The activity of decarboxylating NADP-malatedehydrogenase (E. C. 1.1.1.40) in green ethiolated pea and barley leaves and in green leaves of a pea mutant lacking photosystem II is found to be 3-fold increased after the injection of malic acid into cut plants. Protein synthesis inhibitors depressed malic acid-induced increase of the activity of "malic"-enzyme, the effect of chloramphenicol being more pronounced in ethiolated green leaves, and that of cycloheximide--in leaves of a mutant with formed photosynthetic apparatus. Possible dependence of malate-induced biosynthesis of "malic"-enzyme on the degree of NADP reduction in chloroplasts is discussed.

Various concentration of fructose-1.6-diphosphate, malate, oxaloacetate, creatine phosphate, ATP, ADP and AMP were studied for their effect on the activity of A4-and B4-isoenzymes of lactate dehydrogenase (LDH, EC 1, 1. 1. 27) produced from skeletal muscles and unfertilized egg cells of Misgurnus fossilis in the reactions of lactate oxidation and pyruvate reduction. It was found that oxaloacetate, creatine phosphate, ADP and AMP decreased the activity of A- and B-type isoenzymes to a different extent. The value of the inhibitory action depended not only on the concentration of the substances and subunit composition of the isoenzymes but also depended on the direction of the reaction they catalyse. Malate and fructose-1.6-diphosphate did not inhibit the activity of A4 isoenzyme in the lactate oxidation and malate and ATP did not influence the activity of the former and of B4-isoenzymes in this reaction. At the same time malate, fructose-1.6-diphosphate and ATP decreased the activity of the investigated isoenzymes in the pyruvate reduction reactions.

The effect of serotonin and malate benzyl hydrazine (inhibitor MAO) on the activity of glutathione peroxidase and intensity of ascorbate-dependent peroxidation of lipids in mitochondria was investigated. Serotonin injected intraperitoneally at a concentration of 20 m/kg increased activity of glutathione peroxidase in liver mitochondria and nonfermented ascorbate-dependent peroxidation of lipids in heart mitochondria. In experiments in vitro serotonin and malate benzyl hydrazine decreased activity of glutathione peroxidase an inhibited nonfermented ascorbate-dependent peroxidation in mitochondria of the heart and liver of rats.

Addition of 150 mg of malic acid per a day to food of rabbits caused an increase in content of reduced ascorbic acid and pyruvic acid in blood; at the same time the content of oxydized forms of ascorbic acid was decreased. Similar alterations were observed in urine of guinea-pigs, which received 100 mg of malic acid per a day. The data obtained suggest that under these conditions the increased reduction, of ascorbic acid was due to increased formation of NADP with H2 in the course of reaction, catalyzed by malate dehydrogenase.

In experiments on guinea pigs it is shown that a preliminary intraperitoneal administration of monoamine oxidase inhibitors (MAOI) -- transamine (10 mg/kg) or malic acid benzyldihydrazide (50 mg/kg) antagonizes the local anesthetic action of celnovocaine (CC) and novocaine (NC). An analogous effect is also observed following instillation of transamine (a 0.1% solution) and malic acid benzyldihydrazide (a 0.23% solution) into the eye 10 minutes before administration of the anesthetic. Instillation of a 0.1% serotonin creatinine sulphate solution also antagonizes anesthesia produced by CC and NC, while MAOI potentiates the effect of serotonin.