[Phenotypic characteristics of factor expression induced by hypoxia and redox status of the rat neocortical cells at different stages of adaptation to hypoxia].

Hypoxic preconditioning induces two-phase increase of HIF-1alpha expression in the neocortex of low-resistance rats. The first, brief phase appears after each hypoxic episode and rapidly disappears in normoxic conditions. The second increase in of HIF-1alpha expression occurs in 24 hours after the hypoxic episode. The phase-nature of HIF-1alpha expression corresponds to the dynamics of urgent and long-term resistance in low-resistance rats, which suggests the HIF-1alpha involvement in mechanisms of urgent and long-term adaptation. It was found that in the mode of preconditioning, hypoxic treatments mobilized the anti-oxidant system (activated Cu, Zn-SOD) and had no effect on the intensity of lipid peroxidation processes in neocortex (INH, 10% O2) or even decreased the content of lipid peroxidation products and oxidized glutathione in neocortical cells in the early post-hypoxic period (HBH-5000, 10.5% O2). Thus, ROS do not play a key role in the induction of HIF-1alpha expression and fast-response/long-term adaptation to O2 deficiency in hypoxia-sensitive animals. In high-resistance rats, hypoxia preconditioning does not influence the HIF-1alpha protein expression and the adaptation. Severe hypoxic modes (HBH-7000, 8% O2) caused activation of lipid peroxidation processes in neocortex of hypoxia-sensitive rats. With the pro-oxidant systems dominating over the anti-oxidant ones, the neocortical expression of HIF-1alpha was found to decrease, which was accompanied by the impairment of the mechanisms of fast-response/long-term adaptation to hypoxia.

[Mithochondria signaling in adaptation to hypoxia].

A bioenergetic mechanism for development of urgent adaptation to hypoxia is considered. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia necessary for 1) succinate- related energy synthesis in conditions of oxygen deficiency and formation of urgent resistance in the body; 2) succinate- related stabilization of HIF-1alpha and initiation of its transcriptional activity related with formation of urgent and long-term adaptation; 3) succinate- related activation of a succinate-specific receptor GPR91. Therefore succinate is a signaling molecule, and its effects are realized at three levels in hypoxia, intramitochondrial, intracellular and intercellular.

[The regulatory role of mitochondrial dysfunction in hypoxia and its interaction with transcription activity].

The mitochondrial respiratory chain participates in the performance of the signal system, which activates the realization of metabolic compensatory processes and coupled functional response to both single and repeated, long-term exposure to acute hypoxia. Under the conditions of reduced oxygen delivery to cells the mitochondrial respiratory chain is involved in the process of oxygen homeostasis regulation and modulates oxygen consumption, the rate of oxygen delivery from the extracellular milieu to mitochondria, and energy synthesis, activating hypoxia-specific transcription factors as well.

[Energotropic, antihypoxic, and antioxidative effects of flavonoids].

Phytogenous flavonoid-containing agents (PFCA) are able to initiate electron flow bypassing the NAD-dependent region of respiratory chain, which is related with the activity of DT-diaphorase catalyzing two-electron reduction of quinones to hydroquinones and hydrogen peroxide in the presence of NADH and oxygen. This property is dramatically potentiated under the conditions of suppressed electron transport function of mitochondrial enzyme complex I (MEC I). In this process, part of the flow goes to the cytochrome region of respiratory chain and provides recovery of the MEC II and MEC III coupling function. The other part forms a flow of free oxidation which can perform as an additional mechanism normalizing the cell redox potential and aimed at decreasing intracellular acidosis under the conditions of MEC I bypassing. The energotropic effect of PFCA under the conditions of blocked MEC I is best evident at low PFCA concentrations. The ratio of coupled to free oxidation in the presence of PFCA depends on PFCA concentration. At low PFCA concentrations and oxidation of NAD-dependent substrates, both pathways become potentiated to an approximately similar extent, although the coupled oxidation pathway is generally activated earlier. At high PFCA doses, the increase in free oxidation pathway predominates and may result in toxic side effects.

[Molecular mechanisms of tissue hypoxia and organism adaptation]. / Molekuliarnye mekhanizmy tkanevoi gipoksii i adaptatsii organizma.

The mechanism for participation of aerobic energy metabolism in formation of urgent and long-term adaptation to hypoxia is under consideration. It is stated that changes in kinetic properties of mitochondrial enzyme complexes (MEC), primarily enzymes of the respiratory chain substrate region (MEC I), in response to oxygen shortage underlie diverse stages of bioenergetic (tissue) hypoxia. It was shown that economization of energy metabolism in adaptation to hypoxia occurs due to formation of a new mitochondrial population. The mitochondria possess lesser size and decreased content of cytochromes; however, they are characterized by higher activities of enzymes and lower affinity of the enzymes to their substrates as well as high efficiency of oxidative phosphorylation. Furthermore the amount of mitochondria increases in the cell. It was demonstrated that oxygen shortage can both directly affect the bioenergetic apparatus of cell and indirectly influence it via stress activation of the neuro-humoral system. The latter triggers a non-specific cascade of functional and metabolic responses and eventually disturbs oxygen delivery to cells, which also promotes bioenergetic hypoxia. Genotypically determined differences in kinetic properties of MEC are established, which play a leading role in formation of the functional and metabolic "portrait" of resistant and non-resistant to hypoxia animals and also in development of urgent and long-term mechanisms of adaptation to hypoxia. It was shown that these mechanisms can be used not only for development of the tactics and strategy for pharmacological correction of hypoxic states, but also for optimization of non-drug methods for enhancing the non-specific resistance of the organism.

[Neurophysiological analysis of the effects of antihypoxic versus psychotropic agents]. / Neirofiziologicheskii analiz deistviia antigipoksantov v sravnenii s psikhotropnymi sredstvami.

The Fourie EEG spectral analysis of thr sensomotor cortex and dorsal hypocampus in freely moving rats could reveal the common pharmacological EEG effects of different antihypoxic agents (gutimin, amtizole, emoxipine, and 3-OPK). All the agents decreased the total EEG power (they all reduced the absolute power in all frequency bands) and simultaneously enhanced (2 relative power. The former suggests that there was a decrease in the energetic level of bioelectric fluctuations, which may indicate that the brain reduces its energetic functioning level. The latter means that antihypoxic drugs activate the central nervous system. This effect may normalize EEG activity during hypoxic conditions, which causes the enhancement of slow-wave activity and reduces fast EEG activity. The pharmacological EEG effects of different groups of psychotropic drugs (nootropic drugs, psychostimulants, antidepressants, benzodiazepine tranquilizers, etc.) versus antihypoxants are discussed.

[Effect of occlusive cerebral ischemia on functional status of the internal organs]. / Vliianie okkliuzionnoi ishemii mozga na funktsional'noe sostoianie vnutrennikh organov.

Biochemical parameters characterizing visceral functions were measured in the plasma of rats with brain ischemia induced by double occlusion of the carotid arteries. Functional insufficiency of the viscera is gradually forming in the course of occlusive ischemia of the brain. Functional insufficiency of the liver was observed in animals with severe neurological deficiency and subsequent lethal outcome. In rats resistant to ischemia, visceral dysfunctions develop in a certain succession, starting from the pancreas and followed by the myocardium, liver, and kidneys.

[Present-day problems of hypoxia]. / Sovremennye problemy gipoksii.

The basic mechanism of hypoxia is energy apparatus dysfunction which is associated with ensuing inactivation of mitochondrial enzyme complexes (from the substrate to terminal portion of the respiratory chain) in oxygen deficiency, which leads to impairments of aerobic energy synthesis, energy-dependent functions, metabolism, and structure of cells. The effects of hypoxia are realized by two ways: 1) by direct impact of oxygen deficiency on the cellular bioenergy apparatus, followed by its dysfunction (bioenergetic hypoxia); 2) by indirect impact via stressor activation of the neurohumoral link that leads to the trigger of a nonspecific cascade of functional and metabolic reactions, to impaired cell oxygen supply and delivery, which also ultimately favors the development of bioenergetic hypoxia. The sequence of bioenergetic impairments is the major mechanism of any forms of hypoxia and underlies the body's individual resistance to oxygen deficiency. To correct these disorders (to restore cell energy generation processes and to maintain them at the level sufficient to perform energy-dependent functions) is the main task of antihypoxic protection. In this connection, prognostic biochemical criteria of different stages of hypoxia have been developed; a new classification of antihypoxants by the mechanism of their action is proposed by identifying a group of specific energy metabolic correctors; a combined drug therapy policy in oxygen deficiency is substantiated by taking into account the body's phenotypic features.

[New approaches to designing metabolic antihypoxants]. / Novye podkhody k sozdaniiu antigipoksantov metabolicheskogo deistviia.

The paper outlines a concept of recovering the energy-synthesizing dysfunction of the respiratory chain at different stages of hypoxia: at the early stage which shows the disturbances of mitochondrial enzymatic complex I function, their correction is made by using the redox agents shunting the transport of electrons at NADH-CoQ, as well as by means of different succinate-oxidase oxidation activators. At the later stages of hypoxia demonstrating the disturbances of electron transport function at the cytochrome site, their correction is effected by applying CoQ and cytochrome C. The mechanisms of the antihypoxic action produced by antioxidative agents are described. The prospects of searching novel antihypoxants are defined.