Novel bivalent positive allosteric modulators of AMPA receptor.

A positive allosteric modulator of AMPA receptors has been designed using computer-aided molecular modeling techniques. It possessed a record high experimentally confirmed potency in the picomolar concentration range and belongs to a new type of bivalent AMPA receptor ligands containing bicyclo[3.3.1]nonane scaffold. The suggested structure could serve as a basis for further optimization and development of drugs for the treatment of neurodegenerative diseases, cognition enhancement, and improvement of memory.

[Study of the neuroprotective action of hybrid structures based on fullerene C60].

The neuroprotective action of hybrid structures based on fullerene C60 with attached proline amino acid has been studied. Hybrid structures contained natural antioxidant carnosine or addends with one or two nitrate groups. It has been shown that all studied compounds had antioxidant activity and decreased the concentration of malondialdehyde in homogenates of the rat brain. Compound 1, which contained the antioxidant carnosine, has been found to be the most effective antioxidant. All compounds except IV and V inhibited the activity of monoamine oxidase B, while compounds I-IV increased the activity of monoamine oxidase A. All investigated compounds inhibited glutamate-induced Ca2+ uptake into synaptosomes of the rat brain cortex. Compound III, containing two nitrate groups, has been found to be the most effective inhibitor. This compound caused a significant increase of the currents of AMPA receptors (AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid).

[Simultaneous AMPA receptor potentiation and NMDA receptor blockade as strategy for creating effective stimulants for cognitive functions].

New compounds representing derivatives of acyclic isothioureas have been synthesized, which are capable of simultaneously activating AMPA receptors and blocking NMDA receptors. In order to produce cognitive-stimulating effect, of principal importance is the pathway of NMDA receptor blockade produced by the drug. Positive influence is due to the blockade of NMDA receptors either by mechanism of rapid dissociation of intrachannel site or by inhibition of NR2B subunit of NMDA receptor. Substances that only potentiate AMPA receptor currents or only block NMDA receptors have less pronounced effect on memory than substances with ability to simultaneously potentiate AMPA receptor currents and block NMDA receptor currents. Based on these results, it is concluded that the simultaneous potentiation of AMPA receptors and blockade of NMDA receptors may be a new approach to the stimulation of cognitive functions.

[Influence of derivatives of arachidonic and docosohexaenic acids on AMPA receptors in Purkinje neurons and cognitive functions in mice].

The effect of derivatives of arachidonic and docosahexaenoic acids on AMPA receptors in Purkinje cells from the rat cerebellum was studied using the patch-clamp electrophysiological method. It was shown that derivatives of arachidonic acid-arachidonoyl dopamine and docosahexaenoic acid-docosahexaenoyl dopamine and ester of docosahexaenoic acid with ethylene glycol in nanomolar concentrations effectively potentiated the ionic currents caused by activation of AMPA receptors of kainic acid. Ester of docosahexaenoic acid with nitroethylene glycol blocked AMPA receptors, and anandamide (ethanolamide of arachidonic acid) was not effective. A behavioral test showed that docosahexaenoyl dopamine in doses of 0.1-20 mg/kg had no effect on the learning and memory abilities of the animals tested.

[Effects of chronic administration of dimebon on behavior and memory of SAMP 10 mice].

SAMP 10 mice with genetically determined senescence (senescence-accelerated mouse prone 10) aged 16 months demonstrated (in comparison to 3-months old animals of the same strain) the following traits typical of old animal: behavior and memory deficiency, exploratory behavior impairment, and elevated level of anxiety. Dimebon administered for a long period of time with drinking water (1.5 mg/kg over 5 months) produced a positive action upon behavior and memory of 16-months-old SAMP 10 mice, optimized exploratory behavior in the open field test, diminished anxiety in elevated plus maze test, and improved retrieval of passive avoidance reaction.

[Effect of nooglutyl on the behavior and memory of SAMP10 mice with genetically determined accelerated aging].

It is established that SAMP10 mice (senescence-accelerated mice prone 10) with genetically determined accelerated senescence at an age of 9-month exhibit (in comparison to 3-month animals of the same strain) the behavior and memory deficits typical of aged animals, namely, reduced locomotor activity elevated anxiety, and disturbances of memory trace retrieval. Nooglutyl in a dose of 20 mg/kg produces a positive effect on the behavior and memory of 9-month old SAMP10 mice. The observed improvements include optimization of the locomotor activity in the open field test, diminished anxiety in elevated plus maze test, and improved retrieval of passive avoidance reflex.

Effects of delta sleep-inducing peptide on pre- and postsynaptic glutamate and postsynaptic GABA receptors in neurons of the cortex, hippocampus, and cerebellum in rats.

We studied the effect of delta sleep-inducing peptide on GABA receptors of hippocampal and cerebellar neurons in rats. It was shown that delta sleep-inducing peptide considerably and dose-dependently potentiates GABA-activated currents in these neurons and blocks NMDA-activated potentiation in cortical and hippocampal neurons. The peptide modulates activity of presynaptic NMDA receptors, which is seen from changes in (45)Ca(2+) uptake into synaptosomes of the brain cortex after uptake stimulation with glutamate and NMDA.

Effect of interleukin-1beta on NMDA-induced 45Ca2+ uptake by synaptosomes of rat brain cortex.

The effect of interleukin-1beta on presynaptic NMDA receptors was evaluated by studying NMDA-induced 45Ca2+ uptake by synaptosomes from rat brain cortex. Interleukin-1beta inhibited 45Ca2+ uptake by synaptosomes. Our results indicate that interleukin-1beta modulates presynaptic NMDA receptors and is probably involved in the regulation of synaptic transmission in the central nervous system.

[The ultrastructure of the blood-air barrier and of the large (granular) epitheliocytes (type-2 alveolocytes) in patients with acquired defects and ischemic heart disease before and after surgical treatment]. / Ul'trastruktura aérogematicheskogo bar'era i bol'shikh (granuliarnykh) épiteliotsitov (al'veolotsitov vtorogo tipa) u bol'nykh c priobretennymi porokami i ishemicheskoi bolezn'iu serdtsa do i posle khirurgicheskogo lecheniia.

Ultrastructure of air-hematic barrier and efficiency of alpha-tocopherolum use for prophylaxis of toxic effect of oxygen used for artificial pulmonary ventilation (APV) and oxygenation of blood outside lungs were studied in 27 patients with mitral and aortal valve diseases and ischemic disease before the operation and on its stages. Macroscopically unchanged lung regions were studied before the heart-lung apparatus switching, 40-45 minutes after clamping the artery in conditions of disturbed blood circulation and 10 minutes after hemostation in pulmonary artery. 6 patients were treated with 100% oxygen for 30 minutes before APV finishing while the other 6 previously received alpha-tocopherolum. Disturbance of the structure of the outermost cell membrane in type I alveolocytes and endotheliocytes, widening of basal layers and their fibers and disorders in the osmiophilic lamellar bodies were established to determine the severity of condition of patients with mitral valve diseases.

[Histological manifestations of the sparing effect of cooling in heat dissection of the cerebral cortex and liver]. / Gistologicheskie proiavleniia shchadiashchego éffekta kholodovoi zashchity pri teplovom rassechenii kory bol'shogo mozga i pecheni.

A new method of heat dissection of tissues combined with application of cooling was studied experimentally in white rats. Histologic changes of tissues of the cerebrum cortex and the liver wounds were investigated. It was found out that automatic selection of temperature regimen in combination of heat and cold ensured stable effect which was well balanced from the point of view of its depth and prevented overheating of tissues surrounding a wound channel. In comparison with cut wounds the above mentioned method allowed to gain better safety of cells.

[Light optical and electron microscopic changes in striated muscle tissue under the effects of sea water and thymogen in experimental animals]. / Svetoopticheskie i élektronno-mikroskopicheskie izmeneniia v poperechnopolosatoi myshechnoi tkani v usloviiakh deistviia morskoi vody i timogena v éksperimente.

Effect of sea-water with t degrees +4 degrees to +8 degrees C with time of exposure from 30 minutes to 24 hours on pelvic extremities was studied in 200 rabbits, optical and ultrastructural studies were carried out. It was revealed that effect of sea-water causes damage of striated tissues' structure and death of animals. Prophylactic injections of thymogen stabilized ultrastructure and raised survival, if time of exposure did not exceed 12 hours.

[The late results of marking a surgical wound of the brain with tantalum powder]. / Otdalennye resul'taty markirovki operatsionnoi rany golovnogo mozga poroshkom tantala.

Distribution in the organism of the tantalum after its application on the brain surgical wound was studied by light microscopy and atomic-emission spectrum analysis with an induction-linked plasma in patients dying from neuro oncological diseases. It is found that in all cases a partial tantalum migration into various brain regions and internal organs occurs. Blood cells are able to fix the tantalum particles in vivo and in vitro, this process being enhanced after a preceding angiography.

[Species and functional differences in NMDA receptors]. / Vidovye i funktsional'nye razlichiia NMDA-retseptorov.

N-methyl-DL-aspartate induced in mice and rats hyperactivity and convulsions. In the mice convulsions effectively suppressed by selected antagonists of NMDA receptors AP 5 and AP 7, and also diazepam and ketamine. But hyperactivity very little attenuated by these substances in high doses. In the rats all these substances on the contrary suppressed hyperactivity and convulsions in the same degree. In the rats hynurenic acid prevented hyperactivity and convulsions. Observations point out to the fact that in mice there are two pharmacological and functional types of NMDA receptors whereas in rats there is only one type which is different from NMDA mice receptors.

[Cytophotometric evaluation of alkaline phosphatase activity in neutrophilic granulocytes and fibroblasts during wound healing in rats]. / Tsitofotometricheskaia otsenka aktivnosti shchelochnoi fosfatazy v neitrofil'nykh granulotsitakh i fibroblastakh pri zazhivlenii ran u krys.

The most informative indexes of alkaline phosphatase activity in neutrophil granulocytes from the peripheral blood and in neutrophil granulocytes and fibroblasts from the wound were defined in the experimental study carried out on 60 rats. These indexes were used to reveal the relationship between blood system reactions and inflammatory and regeneration processes in the wound tissue. The division of neutrophil granulocytes into three functional groups in accordance with alkaline phosphatase activity was demonstrated to be reasonable. The progress of inflammatory and regeneration processes in the wound tissues was shown to be adequately reflected in changes of both general and relative number of blood circulating neutrophil granulocytes of the third functional group characterized by high alkaline phosphatase activity. The results of the study demonstrate that the cytophotometric method is highly informative. It can be used in the clinical practice for an objective evaluation of the wound healing process as well as for an estimation of the treatment efficacy.

[Action of phosphorus-containing aminocarboxylic acids on neuromuscular transmission in the blowfly]. / Deistvie fosforsoderzhashchikh aminokarbonovykh kislot na nervno-myshechnuiu peredachu u miasnoi mukhi.

The action of a series of phosphonic amino acids--glutamate receptor antagonists--on neuromuscular transmission in blowfly larva was studied under voltage clamp conditions. It was shown that 2-amino-4-phosphonobutyric acid decreases synaptic current in a dose-dependent manner, and 2-amino-7-phosphonoheptanoic acid increases its acting presynaptically. The analysis done shows that sensitivity of blowfly glutamate receptors to phosphonic amino acids differs from that in crustacean and mammalian glutamate receptors.

[Effect of cystamine on the morphology of gunshot wound healing (a light and electron microscopic study)]. / Vliianie tsistamina na morfologiiu zazhivleniia ognestrel'noi rany (svetoopticheskoe i élektronno-mikroskopicheskoe issledovanie).

Electron microscopy and histochemical tests were used to study the effect of cystamine on gunshot wound healing in experiments on 24 rabbits. Cystamine was established to speed up maturation of the granulation tissue, epithelization of the wound surface and to make the period of gunshot wound healing 4-5 days shorter.