[Influence of alpha-lipoic acid on liver glutathione system of healthy and Ehrlich ascites carcinoma transplanted mice].

Influence of alpha-lipoic acid (LA) on liver glutathione system of Ehrlich ascites carcinoma (EAC) transplanted mice was studied. LA causes multidirectional influence on glutathione system of healthy mice. EAC transforms LA influence, strengthening prooxidative effects more expressed at introduction in early terms after inoculation of the tumor. The mechanism explaining realization of LA prooxidative effects as a result of interaction with glutathione system is suggested.

[Nuclear glutathione and its functions].

During recent years the nuclear localization of glutathione has been confirmed and this fraction has been quantitatively determined. The nuclear GSH and the enzymes of its metabolism realize independent and important functions. They considerably differ from functions of hyaloplasmic and mitochondrial GSH. Glutathione interacts with regulatory pathways, involved into signal transmission into the nucleus.

[Glutathione system. II. Other enzymes, thiol-disulphide metabolism, inflammation and immunity, functions].

The great significance of glutathione as a redox regulator and the reducing carrier has been established. There is a clear necessity for subdivision of an independent mitochondrial glutathione subsystem. The data on a specificity of glutathione metabolism in different organs are accumulated. The significance of glutathione system for inflammation and immunity has been proved. The investigations of glutathione system for elucidation of pathogenesis of diseases and its diagnostics are used in medicine.

[Importance of selective A1 agonists for the protection of brain and heart against injuring factors].

Powerful selective A1 agonist N6-cyclopentyladenosine (CPA) effectively protects the brain (upon decapitation) and the heart (upon intoxication by KCl or ethylen glycol tetra acetate (EGTA)) against the action of injuring factors on experimental animals. CPA weakens or removes damages and/or cell death and probably promotes the regeneration of tissue structures and restoration of their functions. Thus, CPA increases the tolerance of the heart and brain with respect to the introduction of two strong toxicants and even upon decapitation. CPA and 5'-N-ethyl carboxamide adenosine (NECA) induce profound hypothermia, which also takes part in the protection. Selective agonists exhibit two different protective effects against injuring factors.

[Glutathione system. I. Synthesis, transport, glutathione transferases, glutathione peroxidases].

Studies of glutathione system in all basic trends have been extended considerably during recent 10-15 years. A series of new metabolic enzymes has been discovered. Many of them are polyfunctional and their new activities have been recognized. The enzymes interact with hormones and signal transduction systems. The studies of intracellular, intercellular and inter organs transports have been considerably advanced. The important achievement consist in unmasking new functions not only by selective substances-analytics but also by gene engineering methods as well.

[The erythrocyte and plasma glutathione system under peptic ulcer].

In erythrocytes and blood plasma of patients with the complicated peptic ulcer and postresectional syndromes there was the increase of conjugated dienes (and in the second group the increase in antioxidant activity). Under these conditions the main change was the sharp and identical decrease in glutathione activity. In patients with uncomplicated peptic ulcer there was sharp increase in erythrocyte and plasma glutathione activity and plasma GSH. In operated but basically healthy patients plasma glutathione peroxidase remained decreased but plasma GSH sharply increased. Evidently complicated peptic ulcer is characterized by decreased functioning of the glutathione system. Activation of this system and the decrease or disappearance of manifestations of oxidative stress are associated with a favorable course of this disease, especially at uncomplicated peptic ulcer. The revealed changes significantly differ from those observed in viral hepatitis, bile excretory treat diseases and strokes.

[Different types of hypoxic preconditioning protect the brain against complete global ischemia].

Different types of hypoxia, including several new models, protect the brain against complete global ischemia. Hypoxic (stay in hermetic chamber without or with consumption of CO2 and H2O exhaled), circulatory (bleeding), hematic (injections of NaNO2, CoCl2, NiCl2) and tissue (histotoxic) hypoxia (K2-malonate injection) increases cerebral ischemic tolerance in early terms (in hours). Intracerebroventricular injections of NaNO2, CoCl2, NiCl2 and K2-malonate in nontoxic doses have weak effects. These substances act by peripheral mechanisms. Increased ischemic tolerance is accompanied by pronounced hypothermia which closely correlates with a neuroprotective effect. This shows using tolerant strategy.

[The blood glutathione system in cerebral vascular diseases and its treatment with alpha-lipoic acid].

The changes of glutathione metabolism are rare in dyscirculatory encephalopathy and ischemic stroke (IS) of mild severity. The frequent and considerable changes have been revealed in IS of moderate and high severity as well as in hemorrhagic stroke. An increase of activities of glutathione peroxidase and glutathione transferase is the most typical. The increase of enzyme activity was not observed at the beginning of treatment after 3 days and in patients with severe degree of disease who died later. A standard therapy decreased the quantity and/or expression of changes of the glutathione metabolism in patients with IS of moderate and high severity while the addition of alpha-lipoic acid (alpha-LA) led to the complete normalization in IS of moderate severity and normalization of most parameters in IS of high severity. The increase of functional activity of the glutathione system at the early stage of treatment of IS and the favorable changes during the treatment, in particular after the addition of alpha-LA, were correlated with the improvement of neurological status assessed with the NIHSS. It has been confirmed that the glutathione system plays an important role in the tolerance to brain ischemia.

[The role of hypothermia in brain protection by adenosine receptor agonists].

Agonists of A1 adenosine receptors induce a profound hypothermia that is correlated with a considerable increase in tolerance with respect to the global cerebral ischemia. Thermal irradiation of the head considerably decreases and the thermoneutral temperature completely prevents (i) the development of hypothermia in the body and, especially, in the cortex and (ii) the neuroprotection, so that a correlation of these two effects disappears. The induction of hypothermia is the most important but not single mechanism of neuroprotective action of A1-receptor agonists. Other A-agonists are much less active.

[Glutathione system in erythrocytes and plasma in viral hepatitis].

In all 5 acute (AVHs) and chronic viral hepatites (CVHs) there was the increase of erythrocyte activities of glutathione peroxidase (GPx) and glutathione reductase (GR), and the decrerase in GSH concentration. In blood plasma there was accumulation of GPx, glutathione S-transferase (GST) and y-glutamyl transferase (gammaGT). GSH and GR increased in plasma only in AVHs. In CVH C erythrocyte GST increased. Evidently changes in the erythrocyte glutathione system are reactions to oxidative stress and in blood plasma they are consequences of inflammation and hepatocyte cytolysis. Changes were more pronounced in middle-heavy course than in the heavy one. These changes have pathogenic importance and can be used in addition to complex diagnostics. They are significantly differed from changes in chronic gall-bladder diseases. Necessity of separate investigation of glutathione system in erythrocytes and blood plasma but not in whole blood is argued.

[5-hydroxytryptamine and 5-methoxytryptamine increase tolerance to global cerebral ischemia].

In the global cerebral ischemia, 5-hydroxytryptamine (serotonin, 5-HT) and 5-methoxytryptamine (5-MT) produce a significant neuroprotector effect closely correlated with their hypothermic action. This expands the spectrum of cerebral functions controlled by 5-HT. At the same time, melatonin and 2-iodmelatonin, which are chemically (but not pharmacologically) close to 5-HT and 5-MT, do not exhibit such protective effects. Probably, an important role in the interaction with 5-HT receptors belongs to the NH2 group of the indole ring.

[Regulation of metabolic and energetic mitochondrial functions by hormones and signal transduction systems].

The discovery of the complex regulation of mitochondria functions by hormones and signal transduction systems is one of the new and important achivements of mitochondriology. A number of hormones of all the chemical classes and with different action mechanisms stimulate many mitochondrial processes, including Krebs cycle, respiratory chain, oxidative phosphorylation, energy dependent syntheses. These effects are realized and/or reproduced by receptors, the second messengers (cAMP, Ca2+, diacylglycerol), protein and tyrosine kinases, anchor proteins, transcription factors. All the main kinases are found in mitochondria; protein kinases and/or tyrosine kinases phosphorylate the protein 18 kDa from complex I, cytochrome c-oxidase, ATP-synthase, protein binding to cAMP/Ca2+ response element, voltage dependent anione channel, steroidogenic acute protein, proapoptotic protein BAD and also other proteins of mitochondrial membranes. Pleiotropy of calcium regulation of mitochondrial functions is proved. The receptors of lipophilic hormone, growth hormone, epidermal growth factor and neurotrophins are discovered in mitochondria. In cellular signaling mitochondria play the integrative role.

[Neuroprotective effect of antipsychotic drugs (neuroleptics) in global brain ischemia].

Most of typical and atypical neuroleptics belonging to various chemical groups produce a significant, dose-dependent increase in the brain tolerance to global ischemia. This activity of neuroleptics is related to their structure and exhibits no correlation with their antipsychotic properties. Therefore, the ability to increase the brain tolerance to global ischemia is an independent property of neuroleptics. The neuroprotective effect is also not correlated with their affinity to serotonin 5-HT2A and dopamine D2 receptors, but is closely related to the development of deep hypothermia. Thermoneutral conditions prevent both effects. Tolerant strategy plays the main role in the development of the neuroprotective effect of neuroleptics.

[Biochemical and pharmacological mechanisms of different types of hypoxic preconditioning in cerebral ischemia in mice].

Different types of hypoxic preconditioning (hypoxic, circulatory, hemic and tissue hypoxia) increase the tolerance to complete global cerebral ischemia at early terms (hours). Biochemico-pharmacological analysis with the use of selective agonists and antagonists showed the importance of adenosine A1-receptors and K+(ATP)-channels in the mechanisms of the neuroprotective effect and natural tolerance. The general scheme of the investigated mechanisms of different types of hypoxic preconditioning has been proposed.

[New approaches to brain protection against global ischemia].

Three pathways to increase tolerance to global cerebral ischemia have been worked out: (1) the use of inhibitory neurotransmitters and their analogues; (2) injection of neuroleptics; (3) hypoxic preconditioning. We revealed the importance of receptors, K(ATP) channels and induction of hypothermia in neuroprotective mechanisms of these influences.

[Influence of the selective ligands of dopamine and 5-hydroxytryptamine receptors on the tolerance to global cerebral ischemia].

Selective dopamine (D) receptor agonists either slightly improve (D2 and D3) or do not affect (D1 and D4) the tolerance of the brain to global ischemia. As for D and 5-HT (hydroxytryptamine) antagonists, only D1 antagonist SCH 23390 and 5-HT2 antagonist ketanserin produce a small neuroprotective effect, while D2, D4, 5-HT(2B) and 5-HT(2C) antagonists are not active. Simultaneous injection of D2 (raclopride), D3 (GR 103691), and D4 (L 745870) receptor blockers also does not protect the brain. These results are not at variance with a widespread hypothesis that the accumulation of extracellular 5-HT and especially D in the brain causes the neuron damage. The effect of ketanserine is not increased by D2 or D4 blockers, but the introduction of D3 blocker GR 103691 (+88%) and especially the simultaneous injection of D2,3,4 antagonists improve the effect of ketanserine (+134%). The neuroprotective effect of the last combination is not lower but even exceeds that of some neuroleptics. This fact shows the possibility to increase the tolerance to cerebral ischemia by simultaneously blocking D and 5-HT-receptors.

[General hormonology]. / Obshchaia gormonologii.

Research of hormones and mechanisms of their action is one of the most rapidly developing branches of modern biology. During the last 15 years it has been shown that hormones regulate all vital processes: metabolism and functions as well as template syntheses and other cellular processes (proliferation etc.), determined by genome. The majority of hormones showed new effects, their action proved to be pleiotropic. The comparative analysis has shown the fundamental uniformity of biological functions and signification, the basic features and properties, molecular mechanisms of action for all types of intercellular receptor regulators' activity. Therefore they are appropriate to be combined into a complete community, so-called "hormones". The science of all hormones is to be defined as hormonology. The activity of hormones considerably changes upon many diseases. Substances, which influence hormonal systems, make 2/3 of modern medications.

[The correlation of tolerance to cerebral ischemia and body temperature with glutathione concentration]. / Vzaimosviaz' tolerantnosti k ishemii golovnogo mozga i temperatury tela s kontsentratsiei glutationa.

Methodic approaches for the purposeful changes of glutathione concentration in the brain and liver by administration of glutathione depletors and prodrugs have been modified. Two different depletors (diethylmaleate and buthionine sulfoximine) cause considerable increase of tolerance to the complete global cerebral ischemia and hypothermia development which correlate closely with the decrease of GSH concentration. Five GSH prodrugs (GSH esters and oxothiazolidine carboxilate) and GSH itself usually decrease slightly body temperature but do not influence tolerance to ischemia in the most of series. The increase of tolerance to the complete global cerebral ischemia is connected not with GSH accumulation, but with its decrease. Evidently one of the two opposite GSH effects, sensitizing or protecting one, can predominate in different forms of cerebral ischemia.

Neuroprotective effect of hypoxic preconditioning: phenomenon and mechanisms.

We developed a new model of hypoxic preconditioning improving tolerance of complete global cerebral ischemia. The role of adenosine receptors in the realization of this effect and in the mechanisms of hypoxic tolerance is demonstrated. Preconditioning decreases of body temperature, which correlates with the neuroprotective effect, but this effect does not directly result from hypothermia.