Bulletin of Experimental Biology and Medicine

Published by Springer Verlag
Online ISSN: 1573-8221
Print ISSN: 0007-4888
Publications
Systemic oral administration of NT-0409, a new synthetic agonist of AMPA subtype glutamate receptor, to rats with chronic partial AF64A-induced deprivation of cholinergic functions improved their learning in a Morris water maze. NT-0409 is close to memantine by the effect on learning and, in contrast to cholinomimetic arisept, ensures longer retention of the developed habit.
 
High levels of macrophages and fibroblasts expressing MMP-2, MMP-9, and MMP-10 against the background of progressing early fibrosis of the lungs (manifesting in an increase in volume density of type I, III, IV, and VI collagens) were found in C57Bl/6 mice infected with influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus. Progressing fibrosis of the lungs in infected mice was associated with imbalance of collagen synthesis and degradation processes conjugated with high levels of macrophages and fibroblasts expressing TIMP-2.
 
Results of Light Microscopy and Morphometry of Fibrous Connective Tissue in the Lungs of C57Bl/6 Mice Infected with Influenza Virus A/H5N1 A/goose/Krasnoozerskoye/627/05 (M±m) 
C57Bl/6 mice were intranasally infected with influenza virus A/H5N1 A/goose/Krasnoozerskoye/627/05. The mortality rate of animals reached 70% on day 14 of the disease. The lungs of animals were characterized by necroses, destruction of vessels, hemorrhagic and thrombotic complications, edematous syndrome, and early fibrosis of the interstitium. On days 6-10 after infection, fibrosis was found in the zones of postnecrotic inflammatory infiltration. The expression of lysozyme and myeloperoxidase by pulmonary macrophages was initially increased, but decreased on day 10 of the study. The number of cathepsin D-expressing macrophages was elevated up to the 10th day of examination.
 
Numerical density (Nai) of lung vascular endotheliocytes in C57Bl/6 mice infected by influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus. *p<0.05: the studied parameter differs significantly from the parameter during the previous term. 
The lung vessels of male C57Bl/6 mice were studied by immunohistochemical and stereometric methods on days 1, 3, 6, and 10 after intranasal infection with influenza A/H5N1 A/Goose/Krasnoozerskoye/627/05 virus. Influenza virus replicates in mouse lung vascular endotheliocytes and persists in these cells until the beginning of convalescence (day 10 after infection). This indicates high pathogenic activity of this strain. Active proliferation and apoptosis of endotheliocytes are detected early after infection; the counts of endotheliocytes expressing lysosomal hydrolases and NO-synthases increase many-fold.
 
Mice C57Bl/6 were intranasally infected with influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus. The expression of influenza A virus antigen in the lung interstitium fibroblasts was recorded during all periods of the study (on days 1-14 after infection), the maximum expression on days 1 and 3. On day 1, the volume density of collagen fibers in the lungs was 3-fold higher than in intact animals; by day 14 it increased almost 15-fold. The numerical density of PCNA+fibroblasts increased almost 2-fold from day 1 to day 10; "fibroplastic activity" of fibroblasts increased more than 3-fold.
 
Anaferon (pediatric formulation) administered in the therapeutic-and-prophylactic regimen to mice receiving intranasally 100% infecting dose of A/California/07/2009(H1N1)v influenza virus exhibited an antiviral effect and 10-fold reduced the production of influenza virus in the lungs of infected mice on days 4, 6, and 8 after infection compared to the control (distilled water). The efficiency of Anaferon (pediatric formulation) administered before and after infection with A/California/07/2009(H1N1)v influenza virus was not inferior to the use of Tamiflu after infection.
 
We studied the effect of homologues derivatives of 1,1-dimethyl-3-hydroxybutyl phosphonic acid on synaptic transmission in frog neuromuscular junction. Here we reviewed general mechanisms of inhibition of the postsynaptic current.
 
In vivo experimental studies showed that 1,2-dimethylhydrazine and product of its metabolism in the body azoximethane improve postradiation survival of two types of stem cells in the adult organism: hemopoietic stem cells and intestinal epithelial stem cells. This effect similar to the well-known radioprotective effect of E. coli lipopolysaccharide was observed, when the carcinogen was administered 1 day before gamma-irradiation. Treatment with 1,2-dimethylhydrazine prolonged the mean life-span of mice irradiated in supralethal doses inducing death of the majority of intestinal epithelial stem cells. Nonspecific cyclooxygenase inhibitor indometacin weakened this radioprotective effect of 1,2-dimethylhydrazine. We also found that carcinogen 1,2-dimethylhydrazine improved survival of hemopoietic stem cells. However, in contrast to intestinal epithelial stem cells, indometacin did not inhibit the radioprotective effect of the carcinogen. The radioprotective effect of 1,2-dimethylhydrazine and lipopolysaccharide on stem cells in the presence of indometacin was a sum of individual effects of these preparations and indometacin.
 
Dose-dependent effect of RU-1117 on [Ca 2+ ] cyt in myocytes. 1) 80 µM; 2) 40 µM; 3) 20 µM; 4) 0 µM. Calcium response was recorded 2 min after addition of RU-1117 to the culture medium. *p<0.05 compared to the control.  
Time course of the effect of RU-1117 (80 µM) on [Ca 2+ ] cyt in myocytes.  
We studied the mechanisms of action of imidazobenzimidazole derivative RU-1117 on calcium homeostasis in myocytes isolated from rat thoracic aorta. In therapeutic concentrations, RU-1117 increased the content of free calcium ions due to their mobilization from intracellular depot via the IP3-dependent mechanisms. Antagonists of angiotensin II AT1-receptors irbesartan and, to greater extent, eprosartan abolished the calcium-mobilizing action of RU-1117. Selective antagonist of endothelin ETA-receptors sitaxsentan and alpha1-adrenoceptor agonist prazosin produced no effect on calcium mobilization caused by novel local anesthetic RU-1117.
 
Dynamis of the content of Thy-1,2 + cells in the bone marrow of CBA/CaLac mice during hypoxic hypoxia (1), hemolytic anemia (2), and blood loss (3). Dotted lines: upper and lower limits of the confidence interval in intact mice, p<0.05.
Growth of erythroid colonies from nonadherent myelokaryocytes (a, b, c) and adherent myelokaryocytes on adherent sublayer (d, e, f) of bone marrow cells of CBA/CaLac mice during hypoxic hypoxia (a, d), hemolytic anemia (b, e), and blood loss (c, f). Here and in Fig. 3: ordinate, colony-forming activity of the bone marrow (per 10 5 myelokaryocytes). Light bars: suspension of complement-treated nonadherent cells (control). Dark bars: suspension of nonadherent cells deprived of Thy-1,2 + cells. Confidence intervals at p<0.05.
We studied the role of Thy-1,2+ cells in the regulation of hemopoiesis during oxygen deficiency of different genesis. These cells of the hemopoiesis-inducing microenvironment play an important role in the compensatory and adaptive reactions of the blood system to hypoxia. Thy-1,2+ cells directly or indirectly (via interaction with adherent myelokaryocytes) stimulated hemopoietic precursors. The effect of these cells on committed erythroid precursors was most pronounced.
 
Number of Thy-1,2 + cells in the bone marrow of CBA/CaLac mice during hypoxic hypoxia (a), hemolytic anemia (b), and blood loss (c) accompanied by encephalopathy (1). Administration of sodium hydroxybutyrate during experimental hypoxia (2). Horizontal line: intact mice. Here and in Fig. 2: confidence intervals at p<0.05.
We studied the state of the bone marrow Thy-1,2(+) cell pool under conditions of severe hypoxia. T cell mechanisms of hemopoiesis regulation are preserved under conditions of severe oxygen deficiency due to changes in functional properties of Thy-1,2(+) cells. We revealed an indirect (mediated through cooperation with adherent myelokaryocytes) stimulating effect of Thy-1,2(+) cells on erythroid precursors as well as direct and indirect feeder effects of these cells on granulocyte-monocyte precursors.
 
Effect of adherent myelokaryocytes on the G-CSF-induced stimulation of growth of CFU-GEMM (a, b, c) and CFU-G (d, e, f) in the culture of nonadherent bone marrow cells from cyclophosphamide-receiving CBA/CaLac mice. Administration of the solvent (a, d), SG-CSF (b, e), and IG-CSF (c, f). Here and in Figs. 2 and 3: ordinate, number of precursor cells in the bone marrow, % of the intact control (IC, 100%). Group without (1) and with adherent myelokaryocytes (2). p<0.05: *compared to the intact control; + compared to 1. 
Effect of Thy 1,2 + cells on the G-CSF-induced stimulation of growth of CFU-GEMM (a, b, c) and CFU-G (d, e, f) in the culture of nonadherent bone marrow cells from cyclophosphamide-receiving CBA/CaLac mice. Administration of the solvent (a, d), SG-CSF (b, e), and IG-CSF (c, f). Light bars, group with Thy 1,2 + cells; dark bars; group without Thy 1,2 + cells. p<0.05: *compared to light bars; + compared to the intact control. 
Effect of G-CSF products on the growth of CFU-GEMM (a) and CFU-G (b) in the culture of nonadherent bone marrow cells from cyclophosphamide-receiving CBA/CaLac mice. Cytostatic control (physiological saline, 1); after treatment with cyclophosphamide and Neupogen (2); after treatment with cyclophosphamide and IG-CSF (3). p<0.05: *compared to the intact control; + compared to 1. 
The effects of immobilized granulocyte colony-stimulating factor (mediated by cells of the hemopoiesis-inducing microenvironment) on hemopoietic precursors of various classes were studied on the model of cytostatic-induced myelosuppression (administration of cyclophosphamide). The action of this preparation was compared with that of the standard preparation of granulocyte colony-stimulating factor. Thy 1,2(+)cells potentiated the effects of immobilized and standard granulocyte colony-stimulating factors on granulocyte-erythroid-macrophage-megakaryocyte precursors. Stromal cells were shown to potentiate the influence of these agents on granulocyte precursors. Induction of proliferation of precursor cells by the immobilized factor mediated by cells of the hemopoiesis-inducing microenvironment persisted for a longer period compared to that induced by the standard product.
 
Number of Thy 1,2 + cells in the bone marrow of CBA/CaLac mice in conflict test (1) and during paradoxical sleep deprivation (2). *p<0.05 compared to the baseline level. 
Number of erythroid colonies from bone marrow cells of CBA/CaLac mice nonadhering (a, c) or adhering to the sublayer (b, d): conflict situation (a, b) and paradoxical sleep deprivation (c, d). Here and in Fig. 3: suspension of nonadherent myelokaryocytes depleted of Thy 1,2 + cells (light bars) or treated with the complement (dark bars). Ordinate: colony-forming activity of the bone marrow (per 10 5 nonadherent myelokaryocytes). p<0.05: *compared to the baseline level; + compared to Thy 1,2 + cell-depleted suspension. 
We studied the direct and stromal cell-mediated effects of bone marrow Thy 1,2+ cells on the growth of granulocyte-macrophage and erythroid colonies from the bone marrow of CBA/CaLac mice with experimental neuroses (conflict situation and paradoxical sleep deprivation). Proliferation and differentiation of hemopoietic precursors during neuroses are controlled by regulatory T cells. In conflict situation Thy 1,2+ cells stimulate the growth of hemopoietic precursors, which is associated with their direct effect and interaction with adherent cells of the hemopoiesis-inducing microenvironment. The interaction of Thy 1,2+ cells with adherent bone marrow cells during paradoxical sleep deprivation stimulates the formation of only granulocyte-macrophage colonies.
 
We studied immediate and delayed effects of intraventricular injection of 1,2-epoxypropyltrimethylammonium chloride on behavioral reactions in rats. Apomorphine-induced yawning increased and orientation and exploratory activity was improved 144 h postinjection, which indicates activation of the brain dopaminergic system during this period.
 
We studied in vitro effects of four 1,2,3,4-tetrahydroimidazo[4,5-c]-pyridine derivatives formed in the reaction of the corresponding aldehydes with histidine on the rate of ethanol oxidation by alcohol dehydrogenase isoforms from human liver. None of test compounds inhibited ethanol oxidation by these enzymes. Some of them increased alcohol dehydrogenase activity to 220-240% of the initial level. Only one test compound accelerated ethanol oxidation by b1b2-alcohol dehydrogenase (150% of the control). The molecular mechanism underlying these effects of 1,2,3,4-tetrahydroimidazo[4,5-c]-pyridine derivatives on ethanol oxidation by alcohol dehydrogenase isoforms from human liver is discussed.
 
Leukocyte count decreased, relative content of neutrophils and monocytes increased, and their phagocytic activity was suppressed in rats with 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced depressive syndrome at the stage of acute behavioral depression. The severity of behavioral depression inversely correlated with changes in the absolute neutrophil and monocyte counts.
 
The dynamics of hypokinesia in male C57Bl/6 mice induced by single administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was studied on the model of parkinsonian syndrome. The neurochemical effect of this neurotoxin was evaluated at the peak of locomotor disorders. Severe hypokinesia was accompanied by an increase in serotonin content and decrease in the rate of serotonin biodegradation in the striatum, hippocampus, and frontal cortex. The content of dopamine metabolite 3,4-dihydroxyphenylacetic acid and dopamine turnover decreased in the striatum, but increased in the hippocampus and frontal cortex. Norepinephrine content decreased in the hypothalamus and cortex. Aspartate content decreased in the hypothalamus and hippocampus.
 
We studied the effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine (2-ADT) on the cardiovascular system in rats with endotoxic shock. Blood pressure, heart rate, and respiratory rate were recorded. E. coli lipopolysaccharide decreased blood pressure and heart rate. 2-ADT in a dose of 5 mg/kg normalized these hemodynamic parameters. The normalizing effect of 2-ADT decreased with increasing the dose of this preparation. 2-ADT in high doses (10, 20, and 30 mg/kg) and repeated injections of the preparation caused death of experimental animals.
 
Glutapyrone belonging to a new type of amino acid-containing 1,4-dihydropyridines produced a protective effect on periodontal tissues and gastric mucosa in rats with different resistance to stress during acute emotional and pain stress.
 
We studied the effect of potentiated antibodies against S-100B antigen on 20% sucrose consumption by Wistar rats under conditions of free-choice drinking from the bowls with sucrose and water during presentation of an acoustic pre-nociceptive or neutral signal. Peroral administration of antibodies after training sessions increased the number and duration of contacts with sucrose solution.
 
We studied consumption of 20% sucrose solution by rats genetically predisposed to catalepsy (GC strain) during training. The consumption of sucrose solution by GC rats was lower in comparison to that in Wistar rats. "Potentiated" antibodies to S-100B antigen administered orally after training sessions increased the number and duration of subsequent contacts of rats with sucrose solution.
 
The micronucleus test was used tu study the possibility of inducing cross-adaptive response in mouse bone marrow cells in vivo with an 850 nm infrared light modulated by a 101 Hz frequency, emitted by a light therapy device "Kurator". We demonstrated that this exposure led to a substantial reduction of cytogenetic cell damage produced by further exposure of animals to X-radiation in the dose of 1.5 Gy, i.e. it induced an adaptive response which did not differ by the magnitude and time course from the adaptive response to radiation.
 
Effect of RS 102221 on the Behavior of Male Mice (M±m) 
Injection of RS 102221 (selective antagonist of serotonin 5-HT2C receptors) in a dose of 2 mg/kg reduced anxiety of mice in the light-darkness test and decreased the amplitude of the startle reflex. RS 102221 in a dose of 1 mg/kg reduced prestimulus inhibition of the startle reflex. No behavioral changes in Porsolt test and motor activity in the open field test were detected. Hence, RS 102221 is characterized by selective anxiolytic activity, and 5-HT2C receptors are involved in the mechanisms of anxiety and startle reflex formation.
 
We studied expression of dystrophin in skeletal muscles of C57BL/10J-mdx mice after transplantation of human embryonic and fetal myoblasts and bone marrow stromal cells. Dystrophin-positive areas corresponding to the location of transplanted cell were detected in muscles of all recipient mice after transplantation of different cell cultures, but the distribution of dystrophin characteristic of normal muscle fibers was detected only after transplantation of embryonic myoblasts. Dystrophin distribution in muscle fibers after transplantation of fetal myoblasts and bone marrow stromal cells was atypical.
 
Comparative analysis of pharmacokinetic parameters of afobazole and its main metabolite M-11 after single intraperitoneal injections of their solutions (25 mg/kg) to rats showed much more intense penetration of M-11 compared to afobazole into rat tissues and organs, judging from the area under the pharmacokinetic curve (AUC) and maximum concentrations (C(max)). The half-life periods (T(l/2e)l) of afobazole and M-11 were similar.
 
The excretion of compound M-11 and its metabolites with the urine and feces was studied in rats after intraperitoneal and oral administration in a dose of 25 mg/kg. Experiments showed that 1% metabolites were detected in excretions over 24 h irrespective of the route of administration, while the initial compound was not found even in trace amounts.
 
11-Deoxymisoprostol (prostaglandin E1 analog) exhibited a pronounced gastroprotective effect on various models of experimental ulcers induced by nonsteroid antiinflammatory drugs. A relationship between high resistance of the gastroduodenal mucosa under the effect of 11-deoxymisoprostol and changes in the level of sialic acid was detected.
 
Therapeutic administration of 11-deoxymisoprostol had a hepatoprotective effect, which manifested in a decrease in the content of alanine transaminase and aspartate transaminase in blood plasma, and produced a choleretic effect in rats with CCI4-induced toxic hepatitis.
 
Acute stress was accompanied by reduction of 11-dehydrocorticosterone to corticosterone in male rats. The reverse reaction predominated during repeated stress and increased after administration of dehydroepiandrosterone sulfate. Treatment with mu-opioid receptor antagonist naltrexone in a dose of 0.1 mg/kg 20 min before administration of dehydroepiandrosterone sulfate abolished this effect.
 
Basic and reactive characteristics of EEG in children of 6-11 years were studied under conditions rhythmic photostimulation. We showed that the efficiency of photostimulated entrainment reaction determines functional maturity of the corresponding brain oscillators.
 
Antiamnestic effect of acyl-prolyl-containing dipeptide GVS-111 was demonstrated in rats with bilateral compression-induced damage to the frontal cortex. Both intraperitoneal and oral administration of the dipeptide improved retrieval of passive avoidance responses in rats with compression-induced cerebral ischemia compared to untreated controls.
 
Cerebellar granule cells in 7-day cultures in control (a), 2 h after 60-min ischemia (b), and after ischemia in the presence of GVS-111 (c). Pyknotic nuclei are indicated by arrowheads. Vanadium hematoxylin staining. Scale bar 20 p. 
Argon anoxia and glucose deprivation were used for modeling of ischemic damage in the cultures of cerebellar granule cells. Protective effect of peptide piracetam analogue GVS-111 was demonstrated. GVS-111 prevented neurodegeneration induced by glutamate and oxidative stress. In contrast to GVS-111, piracetam did not attenuate neurocytotoxic effect of glutamate.
 
Experiments on rats trained passive avoidance task showed that N-phenyl-acetyl-L-prolyl-glycyl ethyl ester, peptide analog of piracetam (GVS-111, Noopept) after oral administration retained antiamnesic activity previously observed after its parenteral administration. Effective doses were 0.5-10 mg/kg. Experiments on a specially-developed model of active avoidance (massive one-session learning schedule) showed that GVS-111 stimulated one-session learning after single administration, while after repeated administration it increased the number of successful learners among those animals who failed after initial training. In this respect, GVS-111 principally differs from its main metabolite cycloprolylglycine and standard nootropic piracetam.
 
Male Wistar rats were maintained for 2 weeks on a semisynthetic ration with 0.4% rutin or on the same ration with 0.4% rutin and Lactobacillus casei 11,4001 suspension in physiological saline in a dose of 2 x 10⁹ CFU per rat. Addition of Lactobacillus casei 114001 potentiated biological activity of rutin. Its antioxidant efficiency increased due to more pronounced increase in antioxidant capacity of the plasma, decrease in plasma content of LPO products, and more pronounced increase in reducing activity and antioxidant capacity of the cytosol of the liver and intestinal mucosa. The probiotic sharply increased the capacity of rutin to suppress pro carcinogenic activity of bacterial β-glucuronidase.
 
Pharmacokinetics of an original compound GB-115 (N-phenylhexanoylglycyltryptophan) synthesized on the basis of the structure of endogenous tetrapeptide cholecystokinin-4 was studied by means of high-performance liquid chromatography. Pharmacokinetic parameters were calculated after intravenous and peroral administration of GB-115. Our results indicate that this dipeptide is resistant to peptidases. The absolute bioavailability of GB-115 is 4.65%.
 
Anti-inflammatory effects of GB-115 compound (N-phenylhexanoyl-glycyl-L-tryptophan amide) injected intraperitoneally in doses of 0.1, 1, and 10 mg/kg were demonstrated on the model of ConA- and carrageenan-induced inflammation. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg to C57Bl/6 female mice with experimental autoimmune encephalomyelitis significantly alleviated the pathological symptoms, improved spontaneous locomotor activity, promoted recovery of thymus weight, and reduced edema and neutrophil infiltration of the perivascular space of the brain tissue. Intraperitoneal injection of GB-115 in a dose of 1 mg/kg suppressed generation of active oxygen forms by neutrophils in the chemiluminescence test.
 
The anxiolytic effects of GB-115, a retroanalogue of cholecystokinin-4, administered orally to outbred and inbred animals with different level of emotionality, were studied in the open field test and elevated plus-maze test. The anxiolytic effect of talanax was observed in outbred mice (0.1-0.5 mg/kg) and in inbred BALB/c mice (0.1 and 5.0 mg/kg) in the open field test. GB-115 increased the time of entries into open arms in outbred rats (0.5-0.7 mg/kg) and in BALB/c mice (0.1 mg/kg). These data confirmed the dependence of GB-115 effect on the phenotype of emotional stress response and demonstrated a shift of anxiolytic doses of the preparation from 0.006-0.100 mg/kg in intraperitoneal administration to 0.1-5.0 mg/kg in oral treatment.
 
We studied the effects of a new dipeptide with anxiolytic activity (GB-115, N-phenylhexanoyl-glycyl-L-tryptophan amide) on parameters of the immune in intact mice and in animals with secondary immunodeficiency caused by cyclophosphamide. GB-115 in doses of 0.1-10 mg/kg stimulated phagocytic activity of peritoneal macrophages and humoral immune response in intact mice. GB-115 exhibited immunocorrecting activity in animals with secondary immunodeficiency.
 
The study examined the antinociceptive potency of dipeptide compound GB-115 (amide N-6-phenylhexanoyl-glycyl-L-tryptophan) during thermal and chemical noxious stimulation of mice. Peroral administration of GB-115 (0.1-20 mg/kg) decreased the incidence of abdominal contractions induced with intraperitoneal acetic acid (0.75%). This effect was comparable to that of sodium diclofenac (20 mg/kg); it was only partially antagonized with naloxone indicating the presence of significant non-opioid component in analgesic effect of GB-115. Ability of this dipeptide to moderate the nociceptive response in tail flick test under a non-selective blockade of the opioid receptors with naloxone and the absence of similar analgesic potency assessed in the hot plate test attest to predominant effect of GB-115 on spinal opioid receptors.
 
Experiments on outbred mice showed that compound GB-115, a retropeptide analogue of the tetrapeptide cholecystokinin, produced a naloxone-dependent potentiating effect on morphine-induced analgesia in the hot-plate test, but did not modulate animal behavior in the tail-flick test in outbred mice. This potentiation of antinociceptive activity of morphine was probably related to the interaction of GB-115 with supraspinal opioidergic mechanisms.
 
We studied the effect of dipeptide GB-115, a retroanalogue of cholecystokinin-4 with anxiolytic properties, on the behavior of outbred rats and BALB/c and C57Bl/6 mice induced by cholecystokinin-4 receptor agonists and yohimbine. Anxiogenic agents were shown to cause anxiety in rats and C57Bl/6 mice (with an active response to stress) in the open field test and elevated plus maze test, but did not modulate the behavior of BALB/c mice exhibiting a freezing response to emotiogenic exposure. Activation of cholecystokinin-4 type 2 receptors abolished the antianxiety effect of GB-115 in BALB/c mice. This dipeptide prevented the development of cholecystokinin-4-induced anxiety in C57Bl/6 mice and outbred rats. α(2)-Adrenoceptor antagonist yohimbine did not modulate the effects of GB-115 in BALB/c mice. GB-115 did not prevent the development of yohimbine-induced anxiety in C57Bl/6 mice. Our results confirm the data on phenotype-specific activity of GB-115. We conclude that cholecystokinin-4 and GB-115 have a common pharmacological target.
 
Time of the Decline of Blood Flow Velocity in the Carotid Artery of Rats with Electrical Stimulation-Induced Thrombosis after Oral Administration of Sbt-119 and Ticlopidine (M±m) 
Antithrombotic properties of a new P2Y1 receptor antagonist N-[(1-morpholinopropyl-amino)- carbonyl-2-(1-ethyl-1H-indole-3-yl)-vinyl]-4-methylphenyl-amide hydrochloride, substance Sbt-119, and reference drug ticlopidine were studied on experimental models of arterial and systemic thromboses. Substance Sbt-119 was 39.9% (p<0.05) more potent than ticlopidine in producing the antithrombotic effect. Moreover, substance Sbt-119 was shown to increase the survival rate of animals after systemic treatment with ADP (by 20%, p<0.0001). This substance decreased the number of mural thrombi and reduced the severity of hemodynamics disturbances in the organs during systemic thrombosis.
 
Corticosterone/11-dehydrocorticosterone ratio in blood plasma. Here and in Fig. 2: light bars, WAG rats; dark bars, NISAG rats. *p<0.05 compared to control rats.
11β-Hydroxysteroid dehydrogenase activity in the kidneys of NISAG rats (rat strain with hereditary stress-induced arterial hypertension) was 1.5-fold higher than in WAG rats. An inverse relationship was observed in the liver of these animals. After stress exposure 11β-hydroxysteroid dehydrogenase activity remained unchanged in the kidneys of NISAG and WAG rats, but significantly increased in the liver of NISAG rats. Functional activity of 11β-hydroxysteroid dehydrogenase probably reflects the hypertensive state of NISAG rats.
 
Content of Corticosteroids and Activity of 11β-HSD in the Adrenal Glands in the Course of Experimental Diabetes (M±m) 
We studied activity of the key enzyme of the pre-receptor metabolism of glucocorticoid hormones, 11β-hydroxysteroid dehydrogenase, in rat adrenal glands, renal cortex and liver in the course of development of alloxan diabetes (9, 20, and 28 day). The enzyme activity was increased 3-4 fold in the adrenal glands throughout the experiment. At the same time, according to the adrenal gland level of corticosterone, its precursor 11-deoxycorticosterone and reversible metabolite 11-dehydrocorticosterone, activity of the second isoform of the enzyme dominated at the early stages of diabetes, and that of the first isoform, at later stages. In long-term diabetes (28 days), along with reduced synthesis of corticosterone and production of 11-dehydrocorticosterone in the adrenal glands, the extra-adrenal formation of corticosterone was activated as indicated by enhanced activity of the first isoform in the liver and that of the second isoform in the kidneys. These changes in activity of the enzyme isoforms promote local formation of corticosterone from its reversible metabolite in the liver and persisting hyperglycemia in diabetes.
 
RU-1203-induced norBNI-irreversible inhibition of sodium (INa), calcium (ICa), and slow and fast potassium currents (IKs and IKf) was demonstrated in isolated neurons of Lymnaea stagnalis.
 
Experiments on male hybrid mice demonstrated that specific immunotherapy with preparations based on carcinoembryonal antigen and mucin containing CA 125 antigen was not associated with general toxicity, local irritating effect, and hepatorenal dysfunction. The absence of toxicity is apparently due to the fact that antigens injected intramuscularly or subcutaneously virtually do not enter the blood. Injections of preparations based on carcinoembryonal antigen and mucin containing CA 125 antigen to mice induced a standard immune response with predominance of class M immunoglobulins during the early terms and class G immunoglobulins at later terms.
 
Experiments in CBA mice with transplanted CaO 1 ovarian carcinoma possessing common antigenic determinants with human ovarian carcinoma showed that specific immunotherapy with mucin containing CA 125 antigen inhibited tumor growth by 60% and prolonged animal lifespan by 40-60% in comparison with the control. The correlation coefficient between the tumor size and antibody titer after injection of mucin was -0.4 for IgM and -0.6 for IgG. Titration of IgG may be used for monitoring of the efficiency of specific immunotherapy.
 
A new etiopathogenetic concept of psoriasis is proposed, which considers psoriasis as a typical inflammatory process characterized by increased antioxidant activity and overexpression of apoptotic receptors. Under these conditions, hyperstimulation of germinative layer cells proliferation dramatically accelerates keratinocyte passage towards apoptotic effect of atmospheric oxygen and its reactive species dooming to death cells with enhanced expression of apoptotic receptors. Oxidative stress of nondifferentiated keratinocytes triggers the formation of defective horny layer, the key mechanism of psoriasis.
 
We studied the effect of terahertz radiation at atmospheric oxygen frequency 129 GHz on blood nitrite concentration in different types of experimental stress against the background of administration of nonselective inhibitor of constitutive NO-synthases. Normalizing effects of radiation on blood nitrite dynamics in animals with acute stress was shown after 15-min exposure and in animals with chronic stress after 30-min exposure. No positive effect of terahertz radiation was observed on altered blood nitrite concentration in male rats after preliminary administration of nonselective constitutive NO-synthase isoform inhibitor L-NAME.
 
Distribution of Frequencies of Alleles and Genotypes of CYP2E1 Polymorphisms in Examined Groups 
We studied the association between of cytochrome P450 2E1 (CYP2E1) gene polymorphism and risk of essential hypertension development depending on alcohol drinking habit in unrelated men in Russian population (patients with essential hypertension and healthy volunteers). All participants were genotyped for four CYP2E1 gene polymorphisms -1293G>C (rs3813867), -1053C>T (rs2031920), 7632T>A (rs6413432), and 9896C>G (rs2070676) by PCR and restriction analysis. We found statistically significant associations between -1293C allele (OR=5.04, 95% CI=1.23-20.70, p=0.03) and -1293GC genotype (OR=5.36, 95% CI=1.28-22.50, p=0.03) with increased risk of essential hypertension in men. Stratified analysis on alcohol drinking habit showed that the presence of -1293C allele (OR=6.82, 95% CI=1.12-41.70, p=0.04) and -1293GC genotype (OR=7.61, 95% CI=1.2-48.4, p=0.03) in men with alcohol abuse increases the risk of essential hypertension. The obtained data suggest that excessive alcohol consumption and increased induction of cytochrome in the carriers of -1293C allele of CYP2E1 gene lead to generation of highly reactive free radical oxidation products. These processes induced oxidative stress and endothelial induction, which served as the pathogenetic basis for essential hypertension.
 
Top-cited authors
Gleb Zyuzkov
  • Russian Academy of Sciences
Vadim Vadimovich Zhdanov
  • Tomsk State University
Elena Udut
  • Siberian State Medical University
Sergei B Seredenin
  • Russian Academy of Sciences
Yuliya Vladimirovna Nesterova
  • Tomsk State University