[The time course of changes in the state of monoaminergic systems in the brain of mice under the acute hypoxia with hypercapnia]. / Dinamika izmenenii sostoianiia monoaminergicheskikh sistem golovnogo mozga myshei pod vliianiem ostroi gipoksii s giperkapniei.

In socially isolated male outbred albino mice, the changes of monoaminergic systems under acute hypoxia with hypercapnia were studied. In cerebral cortex, hippocampus and striatum of the right and left sides of the brain, the concentrations of norepinephrine, dopamine, serotonin and their metabolites - dihydroxyphenylacetic, homovanillic and 5-hydroxyindoleacetic acids were investigated using the HPLC method. In isolated mice, which were not subjected to hypoxia with hypercapnia, higher levels of dopamine and serotonin in the left cortex were found. There was no asymmetry in monoamines and their metabolites in other studied brain structures. 10 min after the onset of exposure, acute hypoxia with hypercapnia resulted in a right-sided increase in norepinephrine levels and a decrease in dopamine levels in the striatum and serotonin levels in the hippocampus. In the cerebral cortex, 10 min after of hypoxic exposure beginning, there was a left-sided decrease in the dopamine content, while the original asymmetry found in the cortex of intact animals disappeared. In isolated mice perished of hypoxia with hypercapnia, almost all parameters returned to the control level. The exception was the ratio of serotonin metabolite level to the neurotransmitter, which in the right cortex became lower than in control animals. In white outbred mice, the brain monoaminergic systems are suggested to be relatively resistant to the negative consequences of hypoxia and hypercapnia, and corresponding shifts resulting in the reflex brain response to changes in the gas composition of the respiratory air.

[The effect of acute hypoxia with hypercapnia on the content of monoamines in symmetrical areas of the brain in albino mice]. / Vliianie ostroi gipoksii s giperkapniei na soderzhanie monoaminov v simmetrichnykh strukturakh golovnogo mozga u belykh besporodnykh myshei.

Changes in the activity of monoaminergic systems of the left and right hemispheres of the brain after acute hypoxia with hypercapnia were investigated in male albino mice. The concentrations of dopamine (DA), serotonin (5-HT) and their metabolites dihydroxyphenylacetic (DOPAC), homovanilic (HVA) and 5-hydroxyindolacetic (5-HIAA) acids were measured by HPLC in the brain cortex, hippocampus and striatum of the right and the left hemispheres. In the control mice not exposed to hypoxia with hypercapnia, a higher concentration of DA in the left cortex was detected. No asymmetry in the content of other substances has been identified in the investigated structures. Acute hypoxia with hypercapnia led to the right-sided increase of DA and 5-HT levels and to the left-sided reduction DOPAC in the cerebral cortex. Under the condition of hypoxia with hypercapnia, in the hippocampus, the left-sided increase of the DA content was revealed. In the striatum the contents of monoamines and their metabolites were insignificantly changed. It has been concluded that acute hypoxia with hypercapnia causes asymmetric changes in monoaminergic systems of the archicortex and the neocortex.

[Central monoaminergic systems sensitivity to acute hypoxia with hypercapnia changes after the maintenance under the long-term social isolation]. / Izmenenie chuvstvitel'nosti tsentral'nykh monoaminergicheskikh sistem k ostroi gipoksii s giperkapniei pod vozdeistviem dlitel'noi sotsial'noi izoliatsii.

The experiments were performed in male albino outbred mice kept in a group and under the conditions of long-term social isolation. The changes in the monoaminergic systems of the left and right hemispheres of the brain after acute hypoxia with hypercapnia have been studied. The levels of dopamine (DA), serotonin (5-HT) and their metabolites - dioxyphenylacetic (DOPAC), homovanillic (HVA), and 5-hydroxyindoleacetic (5-HIAA) acids - were determined by HPLC in the cerebral cortex, hippocampus and striatum of the right and left sides of the brain. In the control mice kept both in the group and under the conditions of social isolation, a higher content of DA in the cortex of the left hemisphere has been found. In the other brain structures the monoamine content was symmetric. In the cerebral cortex of the mice in the group, acute hypoxia with hypercapnia led to a right-sided increase in the DA and 5HT levels. At the same time, the DOPAC content decreased in the left cortex. In mice in the group, under the hypoxia with hypercapnia conditions, the DA level in the left hippocampus increased. In the striatum, the content of monoamines and their metabolites did not change significantly. In animals kept for a long time under the conditions of social isolation, hypoxia with hypercapnia no statistically significant changes in the monoamines and their metabolites levels were found. It has been concluded that the preliminary maintenance under the conditions of prolonged social isolation changes the reaction of central monoaminergic systems to acute hypoxia with hypercapnia.

Effects of Oxytocin on the Levels and Metabolism of Monoamines in the Brain of White Outbred Mice during Long-Term Social Isolation.

The effects of intranasal administration of oxytocin on the levels and metabolism of monoamines in symmetrical structures of the brain of white outbred mice kept under conditions of long-term social isolation were studied by HPLC. Disappearance of initial right-sided asymmetry in the content of dopamine metabolites in the striatum, increased 5-hydroxyacetic acid content in the right striatum, and disappearance of the initial left-sided asymmetry in serotonin level in the cortex were noted; we also found a decrease in norepinephrine content in the left hippocampus with appearance of asymmetry and higher content in the right olfactory tubercle. It can be hypothesized that minor changes in the serotoninergic and dopaminergic systems against the background of high reactivity of noradrenergic system represent specific response of the brain to oxytocin in aggressive animals.

Oxytocin-Induced Changes in Monoamine Level in Symmetric Brain Structures of Isolated Aggressive C57Bl/6 Mice.

Changes in activity of monoaminergic systems of the left and right brain hemispheres after administration of saline and oxytocin were studied in male C57Bl/6 mice subjected to social isolation. The concentrations of dopamine, norepinephrine, serotonin, and their metabolites dihydroxyphenylacetic, homovanillic, and 5-hydroxyindoleacetic acids were measured in the cerebral cortex, hippocampus, olfactory tubercle, and striatum of the left and right brain hemispheres by HPLC. In isolated aggressive males treated intranasally with saline, the content of serotonin and 5-hydroxyindoleacetic acid was significantly higher in the right hippocampus. Oxytocin reduces aggression caused by long-term social isolation, but has no absolute ability to suppress this type of behavior. Oxytocin reduced dopamine content in the left cortex and serotonin content in the right hippocampus and left striatum. Furthermore, oxytocin evened the revealed asymmetry in serotonin and 5-hydroxyindoleacetic acid concentrations in the hippocampus. At the same time, asymmetry in dopamine concentration appeared in the cortex with predominance of this transmitter in the right hemisphere. The data are discussed in the context of lateralization of neurotransmitter systems responsible for intraspecific aggression caused by long-term social isolation.

[Effect of acute hypoxia with hypercapnia on the content of monoamines in symmetrical brain structures of the BALB/c male mice].

The changes in activity of monoaminergic systems of both the right and the left brain hemispheres of the BALB/c male mice after an acute hypoxia with hypercapnia were studied. The concentrations of dopamine, serotonin and their metabolites dihydroxyphenylacetic, homovanilic and 5-hydroxyindolacetic acids were measured by HPLC in the brain cortex, hippocampus and striatum of the right and the left hemispheres. The more high concentration of serotonin was revealed only in the cortex of the left hemisphere in control mice without hypoxia with hypercapnia. The asymmetry in dopamine level was not registered in all structures studied. Acute hypoxia with hypercapnia decreased the dopamine level in the striatum and the serotonin level both in the hippocampus and the brain cortex. The dopamine metabolites level was reduced in the striatum and in the brain cortex of hypoxed mice: both metabolites in the right brain cortex and only dihydroxyphenylacetic acid in the left br ain cortex. Serotonin metabolism was decreased in all brain structures studied after hypoxia with hypercapnia in mice. Therefore, serotoninergic system of the brain is more sensitive to acute hypoxia with hypercapnia than dopaminergic system.

Effect of amtizol on resistance of SHR mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one cerebral hemisphere.

Antihypoxant amtizol (25 mg/kg) prolonged the lifespan of intact SHR mice by 46.2% under conditions of isolated functioning of one cerebral hemisphere. The effect of amtizol on sham-operated animals was less pronounced: the lifespan of mice was prolonged by just 28.1%. Injection of amtizol to mice with active right hemisphere significantly prolonged the lifespan of experimental animals (by 64.8%). The drug was ineffective under conditions of active left hemisphere: the result coincided with the lifespan of similar mice without the drug injection. Hence, antihypoxic effect of amtizol was largely determined by its effect on the right, but not the left cerebral hemisphere.

[Effect of a new triazinoindole derivative on the functional state of CNS in animals under normoxia and hypoxia conditions].

The influence of the new triazinoindole derivative encoded VM-606 on the individual behavior of rats in the open-field and elevated-plus-maze tests has been studied under normal conditions and after exposure to hypoxia with hypercapnia. It is established that VM-606 at a dose of 50 mg/kg under normoxia conditions reduces emotional anxiety, orientation-investigation activity, and mobility factor, while under hypoxic conditions this drug reduces the severity of behavioral changes in test animals. The experiments on mice showed that the compound studied potentiates the hypnotic effect of hexenal. It is suggested that VM-606 exhibits psychosedative and stress-protector properties, which play a certain role in its antihypoxic effect.

Effect of unilateral inactivation of brain hemispheres on hypoxic resistance in mice.

The effects of unilateral cortical spreading depression on the resistance to acute hypoxia with hypercapnia were studied in male SHR mice. The life-span of mice with active right hemisphere was significantly longer than that of intact, but not of sham-operated (active control) animals. Mice with active left hemisphere differed significantly from intact and active control animals. It seems that the right hemisphere supports the optimal level of resistance to hypoxia with hypercapnia, while the left hemisphere performs the "antihypoxic" function. Additional analysis found no differences between the hemispheres in mice with low hypoxic resistance. The differences between the hemispheres increased with increasing the resistance to hypoxia.

[Delayed effect of 2-amino-4-acetylthiazolo[5, 4-b]indole hydrobromide on physical capability in mice].

The effect of 2-amino-4-acetylthiazolo[5, 4-b]indole hydrobromide (compound VM-605), a new antihypoxic drug and an analog of antihypoxant amtizole, on physical capability was studied in mice under swimming test conditions. The action of VM-605 depended both on the terms of testing upon administration of the drug and on the psychoemotional type of test animals. Maximum increase of the physical capacity in test mice was observed in delayed (up to 72 h) period after drug injection rather than in early (within 1-3 h) period. This increase was more typical of emotionally active and high-stress-resistant mice that were preliminarily selected in open field and forced swimming tests. It is suggested that delayed effects of VM-605 on physical capacity are related to the formation of active metabolites of the drug.

[The actoprotective action of thiazoloindole antihypoxic agents].

A series of 12 compounds belonging to thiazoloindole derivatives possessing the antihypoxic activity were studied in order to reveal their actoprotective properties under usual and complicated (threatbahn running, exhaustive swimming) conditions in rats and mice. Five compounds were shown to protect animals from exhaustive loads in 1 h and 24 h after administration; four compounds produced the same effect under acute hypercapnic hypoxia conditions. In contrast, under the conditions of acute hemic hypoxia, all compound possessing high antihypoxic properties did not affect the physical endurance in rats and mice.

Comparative efficiency of succinate-containing antihypoxants in traumatic toxicosis.

Experiments on Wistar rats showed the development of endotoxicosis 12 h after severe compression injury. Endotoxicosis manifested in disorders in bromosulfaleine excretion from the blood, increase of blood urea, uric acid, creatinine, and potassium levels and aminotransferase activities. Injection of succinate-containing antihypoxants (reamberine, cytoflavin, metaprot plus, succinamic acid 2-amino-4-acetylthiasolo[5,4-b]indole) directly after decompression promoted recovery of liver function, prevented the development of hyperfermentemia and renal failure as a result of reduced blood levels of potassium and non-protein nitrogen. The protective effect of the drugs in traumatic toxicosisdecreased in the following order: metaprot plus>cytoflavin>2-amino-4-acetylthiasolo[5,4-b]indole succinaminic acid>reamberine.

Antihypoxants, thiasolo[5,4-b]indole derivatives, increase exercise performance in rats and mice.

The actoptrotective activity of 12 new antihypoxants of the thiasolo[5,4-b]indole series was studied on the model of treadmill running until exhaustion 1 and 24 h after intraperitoneal injection. Highly active compounds more effective than the reference drugs bemithyl and phenamine were found. They increased exercise performance 1 or 24 h after injection or maintained high performance throughout 24 h.

Protective effect of thiazolo[5,4-b]indole in toxic pulmonary edema.

Antiedematous activity of new thiazolo[5,4-b]indole derivatives containing a fragment of isothiourea and characterized by higher antihypoxic activity compared to known antihypoxants was studied on a model of toxic edema of the lungs in mice. Compounds exhibiting high activity on two models of hypoxia (hypobaric and hemic) better protected from lung edema than compounds active only in hypobaric hypoxia.

[Antihypoxant activity in a series of 2-aminothiazole homologs].

The antihypoxic activity of a series of 2-aminothiazole homologs and the related N-syccinamic acids was studied on four hypoxia models. All 2-aminothiazoles possess antihypoxant properties, which increase with the complexity of the molecular structure. The attachment of a succinic acid fragment at the amino group reduced toxicity, but also decreased the antihypoxant activity of drugs.

[Membrane mechanisms of effects of antihypoxic agents bemethyl and almide on neurons of Mollusca]. / Membrannye mekhanizmy deistviia antigipoksantov bemitila i almida na neirony molliuskov.

Membranotropic effects of the antihypoxants bemithyl and almide, structural analogs of thiobenzimidazole, have been studied on the isolated neuronal preparations of Lymaea stagnalis branchycephalic mollusk. Both drugs in a concentration range of 100-1000 microM produced a reversible, dose-dependent nonselective single-phase blocking action upon the ion channels and completely blocked the channels at a concentration of 10 mM. Therefore, bemithyl and almide are active membranotropic compounds capable (in sufficiently high concentrations) of changing the conductivity of slow sodium, calcium, and potassium ion channels in excitable cells. The protective antihypoxant drug reactions on a systemic level of the organism are probably related to the fact that both drugs in small concentrations are capable of hyperpolarizing the cell membrane, activating the ion channel function, and stabilizing the action potential under hypoxia conditions; in greater concentrations, bemithyl and almide are capable of blocking ion currents, thus reducing the excitability of cells and protecting them from overstress.

[Antihypoxic and antiedemic activity of new condensed indole derivatives]. / Antigipoksicheskaia i protivootechnaia aktivnost' novykh kondensirovannykh proizvodnykh indola.

The antihypoxic and antiedemic activity of a series of new indole derivatives and condensed systems, including pyrimido-, thiazolo-, and triazinoindoles, was studied on the hypobaric hypoxic hypoxia ad toxic lung edema models. Several thiazoloindole and formylindole derivatives prevented the loss of experimental animals under hypoxia conditions and significantly reduced the toxic lung edema development. The pharmacological activity of these compounds was comparable with or exceeded that of the standard antihypoxic and antiedemic drugs.