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Vasil'Eva E.V.,Zakusov Institute of Pharmacology | Kondrakhin E.A.,Zakusov Institute of Pharmacology | Salimov R.M.,Zakusov Institute of Pharmacology | Kovalev G.I.,Zakusov Institute of Pharmacology
Eksperimental'naya i Klinicheskaya Farmakologiya | Year: 2016

Pharmacological effects of intraperitoneal (i.p.) and intranasal (i.n.) administration of heptapeptide selank (300 ng/kg/day for 5 days), known to possess anxiolytic and nootropic properties, were compared by studying the elevated-plus-maze behavior of inbred BALB/c and C57BL/6 mice and measuring the binding of markers to NMDA and GAB A receptors of brain. The anxiolytic and nootropic efficiency of selank administered via both routes was observed only in BALB/c mice, which were characterized by initially reduced exploratory activity and higher levels of anxiety as compared to C57BL/6 mice. In BALB/c mice, i.p. selank increased the number of [G-3H]SR 95531 binding sites with GABA-receptors in the frontal cortex by 38 %, without change in binding to NMDA receptors in the hippocampus. On the contrary, i.n. selank led to an increase in the density of [G-3H]MK-801 binding sites by 23 % with no effect on GABA receptors. It is suggested that the differences in pharmacological spectra observed for the two routes of selank administration are determined by specific features of drug pharmacokinetics and biotransformation as well as by the dynamics of formation of the anxiolytic and nootropic effects of selank.


Medvedev A.E.,RAS Institute of Chemistry | Buneeva O.A.,RAS Institute of Chemistry | Kopylov A.T.,RAS Institute of Chemistry | Tikhonova O.V.,RAS Institute of Chemistry | And 4 more authors.
Biochemistry (Moscow) | Year: 2017

Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient (“global”) elimination of damaged organelles and whole damaged cells. © 2017, Pleiades Publishing, Ltd.


Turilova A.I.,Zakusov Institute of Pharmacology | Gan'shina T.S.,Zakusov Institute of Pharmacology | Avdyunina N.I.,Zakusov Institute of Pharmacology | Pyatin B.M.,Zakusov Institute of Pharmacology | Mirzoyan R.S.,Zakusov Institute of Pharmacology
Eksperimental'naya i Klinicheskaya Farmakologiya | Year: 2016

Based on the results of experiments on nonlinear white awake male rats it is established that 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate and mexidol exhibit a pronounced antiarrhythmic (antifibrillatory) activity on the calcium chloride arrhythmia model. The maximum effect was observed for hemisuccinate 2-ethyl-6-methyl-3-hydroxypyridine. This substance, unlike mexidol, also showed high activity on the model of aconitine arrhythmia, which is typical of class I antiarrhytmics. Mexidol did not show this activity. Consequently, 2-ethyl-6-methyl-3-hydroxypyridine hemisuccinate possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I (lidocaine, procainamide) and is comparable in this respect with class IV drug verapamil.


Khlebnikova N.N.,Institute of General Pathology and Pathophysiology | Kushnareva E.Y.,Institute of General Pathology and Pathophysiology | Kudrin V.S.,Zakusov Institute of Pharmacology | Krupina N.A.,Institute of General Pathology and Pathophysiology
Neurochemical Journal | Year: 2014

Using a model of the anxious-depressive state in rats induced by postnatal administration of the inhibitor of dipeptidylpeptidase-IV, methionyl-2(S)-cyanopyrrolidine, we revealed an increase in the metabolism of 5-OTP (which was evaluated using the 5-OIAA/5-OTP ratio) in the frontal cortex. In addition, we found a decrease in DA metabolism in the hypothalamus, which was seen as a decrease in levels of the HVA and (DOPAC + HVA)/DA ratio, and a decrease in the DA content in the hippocampus. A 10-day administration of the tricyclic antidepressant imipramine at a dose of 10 mg/kg or a non-competitive inhibitor of prolylendopeptidase, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, at a dose of 2 mg/kg prevented the development of depressive symptoms and alterations of monoamines and their metabolism in the rat brain. © 2014, Pleiades Publishing, Ltd.


Belov O.V.,Joint Institute for Nuclear Research | Belokopytova K.V.,Moldova Academy of Sciences | Bazyan A.S.,Russian Academy of Sciences | Kudrin V.S.,Zakusov Institute of Pharmacology | And 5 more authors.
Physica Medica | Year: 2016

Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1 Gy of 500 MeV/u 12C particles with a relatively moderate linear energy transfer (10.6 keV/μm). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to 12C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems’ functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer. © 2016 Associazione Italiana di Fisica Medica


PubMed | Russian Academy of Sciences, Joint Institute for Nuclear Research, Zakusov Institute of Pharmacology and Moldova Academy of Sciences
Type: Journal Article | Journal: Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB) | Year: 2016

Planning of the deep-space exploration missions raises a number of questions on the radiation protection of astronauts. One of the medical concerns is associated with exposure of a crew to highly energetic particles of galactic cosmic rays. Among many other health disorders, irradiation with these particles has a substantial impact on the central nervous system (CNS). Although radiation damage to CNS has been addressed extensively during the last years, the mechanisms underlying observed impairments remain mostly unknown. The present study reveals neurochemical and behavioural alterations induced in rats by 1Gy of 500MeV/u (12)C particles with a relatively moderate linear energy transfer (10.6keV/m). It is found that exposure to carbon ions leads to significant modification of the normal monoamine metabolism dynamics as well as the locomotor, exploratory, and anxiety-like behaviours during a two-month period. The obtained results indicate an abnormal redistribution of monoamines and their metabolites in different brain regions after exposure. The most pronounced impairments are detected in the prefrontal cortex, nucleus accumbens, and hypothalamus that illustrate the sensitivity of these brain regions to densely ionizing radiations. It is also shown that exposure to (12)C particles enhances the anxiety in animals and accelerates the age-related reduction in their exploratory capability. The observed monoamine metabolism pattern may indicate the presence of certain compensatory mechanisms being induced in response to irradiation and capable of partial restoration of monoaminergic systems functions. Overall, these findings support a possibility of CNS damage by space-born particles of a relatively moderate linear energy transfer.


Tyurenkova I.N.,Volgograd State University | Bagmetova V.V.,Volgograd State University | Robertus A.I.,Volgograd State University | Vasil'eva E.V.,Zakusov Institute of Pharmacology | Kovalev G.I.,Zakusov Institute of Pharmacology
Neurochemical Journal | Year: 2015

To study the mechanisms of the action of neuroglutam (beta-phenylglutamic acid hydrochloride, RGPU-135), which is a drug with antidepressant and anxiolytic activities, we examined the influence of the antagonist of GABAA receptors bicuculline (1 mg/kg) and the antagonist of GABAB receptors phaclofen (2 mg/kg) on the type and strength of the effects of neuroglutam (26 mg/kg) in behavioral tests. Anxiolytic effects were examined in the open-field test and dark–light box; antidepressant effects were examined in the tail-suspension test. During combined treatment with neuroglutam and bicuculline, anxiolytic and antidepressant effects of neuroglutam did not occur, i.e., development of these effects requires activation of GABAA receptors. Phaclofen counteracted the antidepressant effect of neuroglutam, which, to a certain degree is related to activation of GABAB receptors. Neuroglutam (26–650 mg/kg) suppressed seizures that were induced by the blockers of GABAA receptors picrotoxin (5 mg/kg) and pentylenetetrazol (90 mg/kg), which reflects its capacity to influence this channel. Analysis of the neuroglutam influence (10–10–10–4 M) on the rat brain GABAA and GABAB receptors by the method of radioligand binding in vitro using tritiated [G3-H]SR95531 (for GABAA) and [G3-H](-)Baclofen (for GABAB receptors) did not reveal direct interaction of neuroglutam with these receptors. Subchronic systemic administration of neuroglutam (26 mg/kg, daily for 5 days) to rats induced an increase in the density of GABAA receptors in the prefrontal cortex, which points to its capacity to modulate the expression of GABAA receptors. These data suggest that one of the aspects of the neuropsychotropic effects of neuroglutam is interaction with the GABAergic neurotransmitter system. © 2015, Pleiades Publishing, Ltd.


Spasov A.A.,Volgograd State University | Yakovlev D.S.,Volgograd State University | Maltsev D.V.,Volgograd State University | Zhukovskaya O.N.,Southern Federal University | And 4 more authors.
Russian Journal of Bioorganic Chemistry | Year: 2016

We studied in vitro the 5-HT2A antagonistic activity of 16 imidazo[1,2-a]benzimidazole derivatives. Using the radioligand method we showed the binding of 9-(2-diethylaminoethyl)-2-(4-methoxyphenyl)imidazo[1,2-a]benzimidazol dinitrate to the 2A subtype serotonin receptor. © 2016, Pleiades Publishing, Ltd.


Povarnina P.Y.,Zakusov Institute of Pharmacology | Vorontsova O.N.,Zakusov Institute of Pharmacology | Gudasheva T.A.,Zakusov Institute of Pharmacology | Ostrovskaya R.U.,Zakusov Institute of Pharmacology | Seredenin S.B.,Zakusov Institute of Pharmacology
Acta Naturae | Year: 2013

Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide bis-(N-monosuccinyl- glutamyl-lysine) (GK-2), was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar concentrations, was efficient in animal models of the Parkinson's disease, ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of 0.01-5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects of subchronic intraperitoneal administration of GK-2 on rat models of the Alzheimer's disease are described in this paper. Dipeptide GK-2 at a dose of 1 mg/kg is found to decrease the habituation deficit induced by the septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to significantly prevent spatial memory impairment in Morris water maze induced by intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide mimetic of NGF, acts on models of the Alzheimer's disease upon systemic administration.©2013 Park-media, Ltd.


PubMed | Zakusov Institute of Pharmacology
Type: Journal Article | Journal: Acta naturae | Year: 2013

Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide bis-(N-monosuccinyl- glutamyl-lysine) (GK-2), was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar concentrations, was efficient in animal models of the Parkinsons disease, ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of 0.01-5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects of subchronic intraperitoneal administration of GK-2 on rat models of the Alzheimers disease are described in this paper. Dipeptide GK-2 at a dose of 1 mg/kg is found to decrease the habituation deficit induced by the septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to significantly prevent spatial memory impairment in Morris water maze induced by intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide mimetic of NGF, acts on models of the Alzheimers disease upon systemic administration.

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