Peculiarities of Immediate Response of Respiratory Chain Enzymes in Rat Cerebral Cortex to Hypoxia.

We performed a complex study of the dependence of immediate reaction of catalytic subunits in mitochondrial enzymes (NDUFV2, SDHA, Cyt b, COX1, and ATP5A) in rat cerebral cortex (the most hypoxia-sensitive tissue) on the severity and duration of hypoxia in vivo and the role of individual resistance of rats to oxygen deficiency in this process. Three types of responses to hypoxia were revealed. The immediate response of mitochondria to oxygen deficiency appeared after its drop by 30-33% relatively to normal atmosphere level. It manifested in up-regulation of NAD-dependent oxidation, i.e., activation of respiratory chain complex I. Further decrease in oxygen concentration by 50% reprogrammed the work of respiratory chain via activation of respiratory chain complex II in parallel with down-regulation of the electron transport function of the respiratory chain complex I. This response was optimal for the expression of adaptation genes and for the formation of immediate tolerance of rats to hypoxia. The greatest drop of oxygen concentration by 60-62% reversed the Krebs cycle promoting recovery of the electron transport function of respiratory chain complex I. Despite this, the energy efficiency of the respiratory chain and the potency to mobilize the rapid adaptation mechanisms degraded due to abnormalities in cytochrome segment of the respiratory chain.

Specific Features of Immediate Ultrastructural Changes in Brain Cortex Mitochondria of Rats with Different Tolerance to Hypoxia under Various Modes of Hypoxic Exposures.

We performed ultrastructural study of cerebral cortex mitochondria in rats with different tolerance to oxygen deficiency (low resistant and highly resistant specimens). Low resistant rats were characterized by the prevalence of mitochondria with lightened matrix due to the nondense packing of cristae. By contrast, mitochondria of highly resistant animals had the dense packing of cristae. The structure of mitochondria underwent adaptive changes at 14-10% O2 in the inspired air. Under these conditions, structural characteristics of the cerebral cortex in hypoxia-sensitive rats resembled those in resistant animals. The decrease in O2 concentration to 8% was accompanied by ultrastructural signs of mitochondrial damage, which correlated with de-energization of the cell and dysfunction of adaptive signaling systems. Ultrastructural features of cerebral cortex mitochondria in animals with low and high tolerance to acute oxygen deficiency confirm the hypothesis that they are associated with two different "functionaland-metabolic portraits".

Effects of flavonoid-containing preparation Extralife on hydrogen peroxide production and functioning of mitochondrial ATP-dependent potassium channel.

Extralife, a Pentaphylloides fruticos extract, in concentrations of 0.005-10 µg/ml dose-dependently increased H2O2 production in rat heart mitochondria in the presence of respiration substrates. Extralife decreased ATP-induced accumulation of H2O2 related to inhibition of mitochondrial ATP-dependent potassium channel. This effect was observed only at low doses of the adaptogen (0.05-3 µg/ml). High doses of the substance (5-10 µg/ml) did not abolish ATP-dependent production of H2O2 and increased the rate of H2O2 generation by the mitochondria. We concluded that Extralife in trace concentrations could activate mitochondrial ATP-dependent potassium channel and decrease H2O2 accumulation in the mitochondria.

Corrective effect of flavonoid-containing preparation Extralife on the development of Parkinson's syndrome.

Oral administration of flavonoid-containing preparation Extralife (daily dose 40 mg/kg) to animals with modeled Parkinson's syndrome considerably improved their survival and the main diagnostic and nosological parameters characterizing the state of locomotor functions. The preparation decreased animal mortality, rigidity, disturbances in dynamic muscular work and coordination of movements, and reduced oligokinesia. Experimental data confirm the involvement of mitochondrial enzyme complex I dysfunction in the pathogenesis of the disease and showed the possibility of by-passing this site of the respiratory chain with Extralife.

Effect of ubiquinone-10 and succinic acid on functional characteristics of erythrocytes in rats with epinephrine toxemia.

Prophylactic dietary intake of synthetic ubiquinone-10, succinic acid, or mixture of these substances prevented disturbances in aggregation and electrophoretic mobility of erythrocytes and inhibited lipid peroxidation in cells of rats with experimental epinephrine-induced toxemia.

Parameters of adenylate pool as predictors of energy metabolism disturbances in hepatocytes during hypoxia.

We studied the dependence of various parameters of adenylate pool in hepatocytes on oxygen concentrations. Isolated cells responded to a decrease in oxygen content in their microenvironment by changes in components of the adenine nucleotide system, which attested to phasic nature of this process. Three ranges of oxygen concentrations differing by the type of changes in the parameters of adenylate pool were distinguished: steady-state range of these parameters; primary changes in the adenylate pool aimed at minimization of energy losses (compensatory stage characteristic of the initial stages of hypoxia); and linear drop of ATP content paralleled by decompensation of the regulatory mechanisms of ATP formation and adenine nucleotide degradation. Hence, parameters of the adenylate pool can serve as predictors of different stages of hypoxia. Differences in the parameters of adenylate pool depending on the level of O(2) in hepatocytes of rats highly and low-resistant to hypoxia indicate that energy metabolism is a mechanism involved in the formation of individual cell resistance to oxygen deficiency. These data suggest that suspension of isolated hepatocytes as an adequate cellular model for experimental studies of the effects of hypoxia on energy metabolism and functional activity of the cell.

Effect of ubiquinone-10 on the blood system in rats exposed to radiation.

The use of synthetic ubiquinone-10 (2 and 10 mg/kg) as a therapeutic food additive normalized the counts of erythrocytes, reticulocytes, and leukocytes and the content of hemoglobin in the blood and inhibited lipid peroxidation in erythrocytes in irradiated rats (3 Gy).

Disturbances in energy metabolism during traumatic shock and their pharmacological correction.

In compression traumatic shock caused by mechanical crushing of the lower limbs and eventuating in death of 80% animals, hemodynamic disorders by the end of day 1 lead to the development of energy deficiency most pronounced in skeletal muscles and less pronounced in the liver and kidneys. Energy production in the brain and heart was not impaired. Inhibition of ATP synthesis correlated with decreased SOD activity in organs, but not always with activation of lipid peroxidation, which can occur without concomitant disorders in energy metabolism (in the heart and brain). Therapy with succinate-containing hydroxypyridine derivative decreased animal mortality to 10%; this treatment did not modify hemodynamic parameters, but normalized energy metabolism in organs and activity of the antioxidant and prooxidant systems. These findings suggest that tissue (bioenergetic) hypoxia plays an important role in the pathogenesis of compression traumatic shock and that antihypoxic drugs are essential components of therapy of this condition.

Behavioral peculiarities and reactions of brain dopaminergic systems in rats with different resistance to acute hypobaric hypoxia.

Locomotor activity in the open field test did not correlate with rat resistance to acute hypobaric hypoxia; there was a correlation between this resistance and rat behavior during acute stress. Immobility was characteristic of rats with low and particularly medium resistance to hypoxia; this reaction can be abolished by antidepressants. by contrast, highly resistant rats were mainly hyperactive. The resistance to hypoxia was associated with extreme parameters of dopaminergic neuron functioning. In low-resistant rats locomotor stereotypia was maximal, while perioral stereotypia was the minimal; highly resistant rats were characterized by an opposite pattern, and medium-resistant rats occupied an intermediate position.

Effects of ubiquinone-10 on energy metabolism and lipid peroxidation in rats with myocardial ischemia.

Preventive and therapeutic intraventricular administration of ubiquinone-10 to male rats with epinephrine-induced myocarditis increased the rate of oxidative phosphorylation, elevated the content of ATP, and inhibited lipid peroxidation in ischemic myocardium.