The effects of imipramine and the inhibitor of prolylendopeptidase benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on the levels of monoamines and their metabolites in the brain of rats with an experimental anxious-depressive state
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.
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.
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.
Tyurenkov I.N.,Volgograd State University |
Bagmetova V.V.,Volgograd State University |
Merkushenkova O.V.,Volgograd State University |
Markina Y.V.,Volgograd State University |
And 6 more authors.
Neurochemical Journal | Year: 2015
It is known that neuroglutam (at 26 mg/kg) potentiates stereotypy that is induced by the agonist of postsynaptic dopamine receptors apomorphine (1 mg/kg), and suppresses catalepsy that is induced by the blocker of postsynaptic dopamine receptors haloperidol (1 mg/kg), which points to its stimulatory influence on dopaminergic neurotransmission. Neuroglutam (26 mg/kg) does not affect the contents of noradrenaline and dopamine (DA) in homogenates of rat brain structures; however, it increases the concentration of the metabolites of dopamine 3,4-dioxyphenylacetic acid (DOPAC) in the frontal cortex and homovanillic acid (HVA) in the hippocampus, which points to its positive influence on the rate of DA utilization, and, in addition, an increase in indices that characterize the rate of DA turnover, viz., DOPAC/DA and HVA/DA in the striatum. We used the method of radioligand binding in vitro with [G-3H]-sulpiride to show that neuroglutam (10−10–10−4 M) does not directly interact with dopamine D2 receptors; however, during subchronic administration (5 days; a single daily dose of 26 mg/kg) neuroglutam promotes an increase in the density of D2 receptors in the prefrontal cortex, which points to its ability to modulate the expression of these receptors. The data from neurochemical and radioligand analysis suggest that both presynaptic (intensification of metabolic DA turnover) and postsynaptic (DA receptors) mechanisms of dopaminergic neurotransmission are involved in the neuropsychotropic action of neuroglutam. Neuroglutam did not influence the strength of hyperkinesia that was induced by the metabolic precursor of serotonin 5-hydroxytryptophan on the content of serotonin and its metabolites in rat-brain structures and did not alter the receptor binding of [G-3H]-ketanserin (an antagonist of 5-HT2A receptors) in the prefrontal cortex both under in vitro conditions and during subchronic administration ex vivo, which points to the absence of direct participation of the serotonergic system in the pharmacological action of the studied drug. © 2015, Pleiades Publishing, Ltd.
Kudryashov N.V.,Zakusov Institute of Pharmacology |
Kalinina T.S.,Zakusov Institute of Pharmacology |
Shimshirt A.A.,Zakusov Institute of Pharmacology |
Korolev A.O.,Zakusov Institute of Pharmacology |
And 3 more authors.
Eksperimental'naya i Klinicheskaya Farmakologiya | Year: 2015
It was studied the anxiolytic properties of 4,6-dimethyl-2-(4-chlorophenyl)-2,3-dihydro-lI-pyrazoIo[4,3-c]pyridin-3-one cbloralhydrate (GIZh-72, 20 mg/kg, i.p.) and afobazole (1 mg/kg, i.p.) in comparison to fluoxetine (20 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) in open-field and marble burying tests on male mice of inbred strains BALB/C and C57BL/6. It is established that GIZh-72 administered both 30 min and 24 h before testing produces anxiolytic effect in the open-field test. The open field anxiety response patterns following GIZh-72 administration differed from these in diazepam or afobazole treated BALB/C mice. This drug also decreased the number of buried marbles in both BALB/C and C57BL/6 mice, the effect being comparable to that of afobazole and fluoxetine. In operant drug discrimination liquid-reinforcement paradigm in male Wistar rats, GIZh-72 failed to antagonize or substitute for the interoceptive stimulus cues of pentylenetetrazole evoking the saline-like responses in the latter case, which was evidence for the absence of properties of a ligand bearing positive modulator sites of GABA-A receptor.