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.

[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.

[Etiological role of the herpes simplex virus in causing cervical cancer]. / Izuchenie étiologicheskoi roli virusa obychnogo gerpesa v vozniknoveniia raka sheiki matki.

The results of the composite virological and immunological examinations of 46 patients with cervical carcinoma (CC) attest to the association of herpes simplex virus (HSV) with neoplastic processes. HSV strains were isolated from the tumour tissue as well as from the cervical canal secretions and blood of 4 patients. A higher level of virus-neutralizing and complement-fixing antibodies to HSV was found in sera from CC patients as compared with the control group of normal women. Antibody to HSV type 2 was found in 38.8% of sera from the patients and 12.6% in the control group. Lymphocytes from CC patients induced blasttransformation reaction to HSV twice as frequently as those from healthy subjects. The virus-specific antigen was found in tumour cells of 36% CC patients in immunofluorescent examinations of smears from the cervix. The presented results are related to the determination of the etiological role of HSV in cervical carcinoma.

[Humoral immunity to herpes simplex virus type 2 in cervical cancer]. / Gumoral'nyi immunitet k virusu prostogo gerpesa tipa 2 u bol'nykh rakom sheiki matki.

The analysis of the results of serological studies revealed differences between the number of positively reacting sera from patients with cervical carcinoma and from normal women. The activity of complement-fixing and virus-neutralizing antibodies in the patients' sera and the frequency of their detection were higher than in the sera from normal subjects. These results in combination with other methods of laboratory examinations may be used for early detection of cervical carcinoma as well as for determination of high risk groups with regard to oncological diseases.

[Finding of the herpes simplex virus by electron microscopic study of the biopsy from a cervical cancer patient]. / Obnaruzhenie virusa obychnogo gerpesa pri élektronno-mikroskopicheskom issledovanii bioptata bol'noi rakom sheiki matki.

The question of a possible etiological role of the family of herpes viruses in generation of human malignancies is discussed. The detection of herpes simplex virus in human tumor by electron microscopic examination of a biopsy sample from a cervical carcinoma patient is another proof of herpes virus association with human malignant neoplasias.

[New antigens induced by herpes simplex virus in human tumors]. / Novye antigeny, indutsirovannye virusom prostogo gerpesa, v opukholiakh cheloveka.

Tissues of malignant tumors of the genitalia (cervix, uterus body, ovary) contain a specific antigen associated with herpes simplex virus type 2 (HSV-2) identical with the antigen of the infected cells. The virus-induced antigen was detected in tissues of cervical carcinoma in 35% of cases, in 15% of tumors of the corpus uteri and in 13% of ovary tumors. HSV-2 was isolated from pathologically altered cervical carcinoma cells in 2 out of 56 cases examined. These facts indicate the presence of HSV-2 genetic information in cells of some tumors. No virus-induced antigen was found in any of the 7 specimens of normal nontumorous tissue examined.

[Morphology of healing of an experimental gunshot wound following primary surgical treatment]. / Morfologiia zazhivleniia ognestrel'noi rany posle pervichnoi khirurgicheskoi obrabotki v éksperimente.

The time-course of healing of a perforating gunshot wound of soft tissues after primary surgical treatment was studied histologically, histochemically and electron microscopically in 24 rabbits. Throughout the observation period (1-28 days) disorders of the microcirculation, inflammatory reaction, degenerative and necrotic changes, disorders of the ultrastructure and metabolic processes in cells were observed in the wound tissues. Morphological changes developed in the zone of molecular concussion the presence of which delayed healing of the gunshot wound and reduced the efficiency of the primary surgical treatment. The experimental results extend current knowledge of the morpho-functional features of healing of gunshot wounds and indicate the proper choice of rational methods for surgical treatment.

[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.

[Physiological features of the wing muscle fibers of Locusta migratoria locusts]. / Fiziologicheskie osobennosti volokon krylovoi myshtsy saranchi Locusta migratoria.

In bifunctional dorsoventral muscle M-120 of the locust Locusta migratoria migratorioides three groups of fibers have been found which differ with respect to their electrophysiological properties. The evoked fast potentials in the fibers of caudal portion differed from fast potentials observed in the fibers of rostral and intermediate portions of the muscle. In the fibers of the caudal and intermediate portions of muscle, not only fast, but other depolarization potentials were also recorded which differ in the amplitude and duration, as well as the inhibitory postsynaptic potentials. It was shown that fibers in these three parts of the muscle differ in their voltage-current properties. It is concluded that different types of potentials are due to peculiarities of innervation and to structural heterogeneity of muscle fibers.

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.