Vol 13, No 2 (2015)


Study of anticonvulsant properties of new antagonists of glutamate receptors

Potapkin A.M., Lebedev A.A., Bychkov E.R., Gmiro V.E., Litasova E.V., Brusina M.A., Piotrovskiy L.B., Shabanov P.D.


The experimental data concerning anticonvulsant activity of new compounds, NMDA (IEM-1921, IEM-1791, IEM-2181) and AMPA (IEM-1460) antagonists, synthesized at the Dept. of NeuroPharmacology, in both NMDA and nicotine models of seizures reproduced in CBA mice are represented in the paper. The maximal anticonvulsant activity in a NMDA model was revealed for IEM-2181, an organic monosalt of alkylconstituted derivative of imidazole-4.5-lbcarbonic acid. IEM-2181 170 mg/kg completely blocked all seizure and behavioral signs of NMDA 170 mg/ kg administered intraperitoneally. At the same time, IEM-1460 (5 mg/kg), an antagonist of AMPA receptors, blocked seizures and behavioral hyperactivity induced by ip administration of nicotine (14 mg/kg). Thus, anticonvulsive activity of new antagonists of NMDA and AMPA receptors was established in models of NMDA and nicotine seizures.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):3-9
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Effect of mother alcoholization on the activity of ghrelin system in prenatal and early postnatal periods of rat offspring

Airapetov M.I., Khokhlov P.P., Bychkov E.R., Sekste E.A., Yakushina N.D., Lebedev A.A., Lavrov N.V., Shabanov P.D.


The purpose of the paper was to study both the desacylghrelin (unacylated ghrelin) level in the blood serum and expression of mRNA ghrelin receptor in the brain structures in ontogeny after chronic alcoholization in rats. The results proved that the prenatal effect of ethanol negatively affected the maturation of dopaminergic and ghrelin systems of the brain as well as involvement of ghrelin system in mechanisms of alcohol dependence formation. The decrease of COMT mRNA expression simultaneoully with the increase of expression of D2 long and short isoforms of dopaminergic receptors and misbalance of ghrelin system were observed. Alcoholization of mothers reduced desacylghrelin level in the blood serum in early postnatal period in offsprings although mRNA expression of ghrelin receptor in the brain was elevated. Chronic alcoholization of adult rats also affected the ghrelin system. In the alcoholiztion process, the reduced contents of desacylghrelin in the blood serum with compensatory increase of ghrelin receptor expression in the brain were registered. After withdrawal of ethanol, the recovery of desacylghrelin level (tendency to normalization) was observed.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):10-13
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Contents of ACTH and CRF in the rat blood serum after administration of orexin A antagonists in experimental alcoholization

Vinogradov P.M., Tissen I.Y., Khokhlov P.P., Bychkov E.R., Lebedev A.A., Shabanov P.D.


In recent years, the role of ghrelin and orexin systems in the formation of alcoholic addiction has been demonstrated. The aim of the present investigation was to compare quantitatively the CRF and ACTH blood concentrations in the forced and chronic models of alcoholization, as well as the assessment of pharmacological action of synthetic and recombinant antagonists of orexin A on the system CRF-ACTH after experimental alcohol abuse. 89 adult male Wistar rats weighing 250-300 g Wistar were used in the experiment. All experimental animals were divided into 10 groups: intact, with chronic and forced alcoholization, with intranasal administration of orexin A antagonists on alcoholization process and agter its withdrawal. The chronic (during 6 months) and forced (5 days by means of elevating doses up to maximal ones) alcoholization slightly increased ACTH and CRF levels in the blood serum. The withdrawal of ethanol decreased the hormones level. Intranasal administration of orexin A antagonists (both synthetic and recombinant) slightly decreased the ACTH and CRF concentrations in the blood, in more degree after the forced alcoholization. In general, the systemic action of orexin A antagonists on the central stress mechanisms were expressed in little degree. The significant disorders in the ACTH-CRF system were not registered also, both after different regimens of alcoholizations and after intranasal administrations of orexin A antagonists.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):14-19
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Orexin A role in mechanisms of reinforcement in the bed nucleus of stria terminalis

Lebedev A.A., Shumilov E.G., Bychkov E.R., Morozov V.I., Shabanov P.D.


The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor OX(1), have demonstrated its involvement in behavioral sensitization, conditioned place-preference, self-administration and reinstatement of drugs abuse. There are dense concentrations of hypocretin receptors, in brain regions implicated in drug reinforcement processes, such as the nucleus accumbens, ventral tegmental area and bed nucleus of the stria terminalis Adult male Wistar rats were implanted the stimulating electrodes to the lateral hypothalamus. Simultaneously, the microcanules were implanted into the BNST to inject the OX(1) receptor antagonist. Rats were trained to perform intracranial self-stimulation. The effects of the OX(1)-selective antagonist SB-408124 on brain stimulation-reward (BSR) were measured. SB-408124 injected into the BNST (1µg/1 µl in volume for each injection.) alone had no effect on self-stimulation of lateral hypothalamus. Amphetamine (1 mg/kg i.p.) potentiated BSR, measured as lowering of BSR threshold and enhancing of BSR frequency. Amphetamine-induced stimulatory effects on intracranial self-stimulation was blocked by injections of SB-408124 into BNST. These data demonstrate that OX(1) play an important role in regulating the reinforcing and reward-enhancing properties of amphetamine and suggest that orexin transmission is likely essential for establishing and maintaining the amphetamine habit in human addicts. However, the observations that OX1 antagonism reduce brain reward and block stress- and cue-induced reinstatement of drug-seeking suggests that this class of compounds may be useful additions to stress-reduction and other behavioral therapies in the treatment of substance abuse disorders.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):20-26
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[D-Lys 3]-GHRP-6, an antagonist of ghrelin receptors, decreases expression of conditioned place preference reaction of ethanol in rats

Vinogradov P.M., Tissen I.Y., Lebedev A.A., Bychkov E.R., Lavrov N.V., Botkin E.A., Shabanov P.D.


Ghrelin is a peptide hormone synthesized and secreted by the stomach into the bloodstream. The greatest attention of neuroscience research is devoted to investigation of acylated form of ghrelin, which is a specific ligand for the receptor subcortical nuclei of the brain. The aim of this study was to analyze the action of ghrelin and its antagonist on the expression of conditioned place preference (СPP) of ethanol. To develop CPP of alcohol we used a two-chamber apparatus. Rats were spent 74 % of time experiment in chamber associated with alcohol. Rats receiving intranasal receptor ghrelin antagonist [D-Lys3]-GHRP-6 (10 µg) reduced the time of staying in the chamber associated with alcohol for 46 % (p < 0.05). Rats treated with intranasal ghrelin spent in the chamber, associated with alcohol, for 60 % of time. Then the extinction of CPP was produced when rats was replaced into the apparatus every day for 7 days without administration alcohol or any substances. On the 7th day of extinction, CPP was not reproduced. But after administration of ethanol on the 7th day CPP was reinstated. Animals received GHS-R1A receptor ghrelin antagonist [D-Lys3]-GHRP-6 (10 µg) and ethanol spent 50 % of time in chamber associated with the administration of ethanol, i.e. CPP was not reinstated. Animals treated with ghrelin, demonstrated a range of reactions from a sharp preference to avoidance of the place associated with ethanol. Thus, the present study shows the important role of ghrelin in the mechanisms of the reinforcing effects of alcohol and demonstrates the prospect for using of ghrelin antagonists in the correction of pathological craving in addictive disordes.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):27-33
pages 27-33 views

Anti-inflammatory and immune stimulating effects of trekrezan in treatment of of inflammatory and degenerative damages of the smooth parodont tissue

Shabanov P.D., Mokrenko E.V.


The oxidative and immune status was assessed in a rat model of inflammatory and degenerative damages of the smooth parodont tissue due to administration of 2 % formaldehyde water solution (0.3 ml) into the smooth parodont tissues. The lipid peroxidation indexes (malonic dialdehyde and dienic conjugates level) were 3.6-5.8-fold higher in the blood serum and parodont tissue in 3 days after inflammation beginning. The inflammation was accompanied by inhibition of lymphokin-producing function of lymphocytes in reaction of inhibition of leucocytes migration with concanavalin A (Con A) by 39 % and with phytohaemagglutinin (PGA) by 37 %. The activity of oxygen-independent microbicide system of phagocytes was decreased by 13 %, that was typical for subacute duration of inflammatory process. The phagocyte number was increased by 26 % and the phagocytosis index by 22 % with decrease of phagocytes participating in phagocytosis by 31 %. The spontaneous NBT-test index was increased by 63 %, and stimulating one by 35 %. Trekrezan administered for 3 days decreased malonic dialdehyde level by 61 %, dienic conjugates level by 68 %, in 2.9-fold increased the concentration of recovered glutatione and superoxide dismutase activity by 79 %. Simultaneously, the elevation of lymphokin-producing function of lymphocytes in reaction of inhibition of leucocytes migration with Con A by 67 % and with PGA by 73 % was registered. Phagocyte activity of neutrophils was increased by 24 %. Phagocyte number equal to middle number of microorganisms phaged by one active neutrophil and phagocytosis index were decreased by 26 % and 14 % respectively. Trekrezan administered orally revealed the same but less significant action. Preliminary administration of lidocaine intragastrally for blockade of gastric afferents did not affect the trekrezan action. Therefore, trekrezan possesses both anti-inflammatory and immune stimulating action. Oral administration of trekrezan induced more weak effect than after intraperitoneal administration and did not depend on activation of gastric afferents.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):34-42
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Polymorphisms of xenobiotic biotransformation genes and their role in individualization of pharmacological therapy and support of humans after heavy psychophysical loading

Kozlova A.S., Pyatibrat A.O., Melnov S.B., Smolnik N.S., Shabanov P.D.


We analyzed the frequency distribution of CYP1A1, EPHX1, GSTM1, GSTP1, GSTT1 genes polymorphisms in 111 persons exposed to high physical and mental stress (elite athletes). Qualifications of sportsmen ranged from candidates for master of sports to world-class athlete. Comparative analysis revealed significant differences between the main group and the comparison group in the frequency of GSTM1, GSTT1, CYP1A1 genotypes, and a tendency to a predominance of genotype GSTP1 Val / Val in the main group.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):43-48
pages 43-48 views

Comparative estimation of anticonvulsant activity of cumarines umbelliferone, obtusifole and Haplofillum obtusifolium grass decoction

Barnaulov O.D.


Obtusifole and umbelliferone had low toxicity after enteral administration. Even high obtusifole doses demonstrated weak anticonvulsant activity in the models of maximal electroshock (MES) and pentamethylentetrasole seizures (LD 100). These coumarines were not effective in the models of strychnine- and thiosemycarboside-induced convulsions. They revealed neurotoxical influence, reducing unconditioned reflex, normal adoptive mice behavior and did not prevent the loss of conditioned passive avoiding reflex (CPAR) after MES. These coumarines did not antagonize with synthetic anticonvulsants. The Haplophyllum obtusifolium grass decoction administered enterally was not toxic, because LD minimal might not be fixed. It had no neurotoxical properties, prevented the loss of CPAR and mortality after MES, elevated tolerance to convulsive-mortal pentamethylentetrasole and strychnine action. So this decoction demonstrated cerebroprotective properties. The use of Haplophyllum obtusifolium in traditional medicines of Asiatic states may not be explained by only coumarines. It is based on cerebroprotective properties of this medicine.
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):49-53
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Prominent Russian pharmacologist N.P.Kravkov and his contribution to the world pharmacology (in memoriam to 150 years from the birth)

Shabanov P.D.


In every field of science there are the proper prominent scientists. In Russia, there was Nikolai Pavlovich Kravkov (1865-1924), a founder of the Russian pharmacology. In the paper, the life and scientific achievements of Professor N.P. Kravkov, headed the Department of Pharmacology, Military Medical Academy, St. Petersburg, were described. N. P. Kravkov carried out significant investigations in pharmacology of gas metabolism, drug toxicology, aged and evolutionary pharmacology, clinical pharmacology (discovery of intravenous and combined narcosis). The main achievement of N. P. Kravkov became the cycle of investigations on isolated organs (ear, heart, lung, spleen, pancreatic gland, thyroid gland, adrenal gland, uterus of the mammalians, head and gills of pike, human fingers, heart and spleen). In these investigations, the rhythmic oscillation of the vascular tonus was proved, the theory of phasic action of pharmacological drugs on tissues, presentations on sensitiveness limits of living protoplasma, possibilities of animation of mummified tissues were postulated. N. P. Kravkov created a large scientific school (S. V. Anichkov, M. I. Gramenitskii, G. L. Shkavera, M. N. Nikolaev, A. I. Kuznetsov, B. S. Sentyurin, V. V. Zakusov, V. A. Valdman).
Reviews on Clinical Pharmacology and Drug Therapy. 2015;13(2):54-71
pages 54-71 views

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