Evaluation of Kagocel Genotoxicity.

Antiviral drug Kagocel in concentrations of 0.0008, 0.004, 0.

The Low Molecular Weight Brain-derived Neurotrophic Factor Mimetics with Antidepressant-like Activity.

The search for new highly-effective, fast-acting antidepressant drugs is extremely relevant. Brain derived neurotrophic factor (BDNF) and signaling through its tropomyosin-related tyrosine kinase B (TrkB) receptor, represents one of the most promising therapeutic targets for treating depression. BDNF is a key regulator of neuroplasticity in the hippocampus and the prefrontal cortex, the dysfunction of which is considered to be the main pathophysiological hallmark of this disorder.

Drug with Neuroprotective Properties Noopept Does Not Stimulate Cell Proliferation.

Effects of Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) on the relative level of proliferation marker Ki-67 and cell cycle parameters were studied in HEK293 and SH-SY5Y cell lines. The previously established multifactorial mechanism of action of the drug includes enhancement of neurotrophin NGF and BDNF expression and increase in HIF-1 activity. The possible mitogenic action of Noopept was estimated by its effect on cell proliferation.

Effect of Antibodies to Glutamate on Age-Related Memory Changes in C57Bl/6 Mice.

Chronic intranasal administration of antibodies to glutamate to aging C57Bl/6 mice improved passive avoidance conditioning, had no effect on horizontal and vertical locomotor activity, but slowed locomotion in the open-field test. Administration of antibodies to glutamate increased the content of dopamine and its metabolites in mouse hippocampus, but had no effect on the metabolism of neurotransmitter amino acids. In the frontal cortex, antibodies to glutamate did not affect neurotransmitter metabolism, but increased the level of both excitatory and inhibitory amino acids without changing their ratio.

Neuroprotective Lithium Salts Protect Pancreatic β-Сells from Damage.

We studied antidiabetic effects and cytoprotective activity of two lithium salts (lithium chloride and lithium carbonate) on the model of streptozotocin-induced diabetes mellitus type 2 in Wistar rats. Using the method of β-cells detection with antibodies to insulin, we demonstrated that streptozotocin reduced the number of β-cells and impaired their morphological structure. Both lithium preparations administered to diabetic animals for 28 days in doses of 10 and 8.

Metabolism of a Novel Anxiolytic GML-1 in Rats.

Metabolism of a novel anxiolytic GML-1 (N-benzyl-N-methyl-1-phenylpyrrolo[1,2-a]pirazin-3-carboxamide) in rat blood plasma was studied by HPLC-mass spectrometry. Three biotransformation products with the corresponding molecular ions were detected. A conclusion was made that the main pathways of GML-1 metabolism are oxidative reactions yielding hydroxylated, methylated, and demethylated metabolites.

Novel Technologies for Dipeptide Drugs Design and their Implantation.

The article is an overview of author's data obtained in the framework of the project "The Creation of dipeptide preparations" at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia.

On the Mechanism of the Cardioprotective Action of σ Receptor Agonist Anxiolytic Fabomotizole Hydrochloride (Afobazole).

Original translational rat model of chronic heart failure provoked by experimental anterior transmural myocardium infarction was employed to examine the preventive action of anxiolytic Afobazole (15 mg/kg/day administered intraperitoneally during the first 15 days after coronary occlusion) on the development of the heart failure assessed in 3 months after infarction. Afobazole prevented the development of pathologic remodeling of the myocardium, maintained its inotropic function, and decreased the plasma level of brain natriuretic peptide known as a biochemical marker of chronic heart failure. In the myocardium, Afobazole down-regulated overexpression of the genes induced in chronic heart failure and assessed by corresponding RNA levels, which code angiotensin (AT1A-R), vasopressin (V1A-R), and glucocorticoid (GR) receptors as well as Epac2 protein.

Specific Features of Depolarization of the Left and Right Atria in Rats with Alcoholic Cardiomyopathy.

Using a translation model of alcoholic cardiomyopathy in rats we showed the presence of an additional abnormal excitation focus in the area of the pulmonary vein lacunae in the left atrium and enhanced heterogeneity of the atrium depolarization pattern. These changes can determine electric instability of the myocardium and induce malignant heart rhythm disturbances including, sudden cardiac death.

Antidiabetic Activity of Afobazole in Wistar Rats.

Using the streptozotocin model of type 2 diabetes mellitus in Wistar rats, we compared antidiabetic activity of anxiolytic Afobazole with that of metformin. Afobazole in a dose of 10 mg/kg reduced streptozotocin-induced hyperglycemia and polyphagia and prevented accumulation of malonic dialdehyde, being not inferior to metformin in a dose of 300 mg/kg, and was even more effective than metformin in body weight recovery, elimination of polydipsia, and preservation of these effects after treatment withdrawal.

Mitigating Effect of Nitrates (Monizol) on Pharmacodynamic Shifts in the Cardiovascular System Caused by Radioprotector Indralin.

We studied the effect of radioprotector indralin (B-190) alone or in combination with monizol on BP and HR in rabbits, reduction of blood supply and spleen weight in rats and (CBA×C57Bl/6)F1 hybrids mice, and on blood loss from a wound on tip of the tail in mice. Being an α1-adrenomimetic, indralin caused hypertensive reaction with the development of bradycardia, reduced blood supply and spleen weight, and sharply reduced blood loss from the wound. Monizol as nitrate reduced BP without affecting HR and reduced blood loss from the wound.

N-(5-Hydroxynicotinoil)-L-Glutamic Acid Calcium Salt Modifies Responses of Rat Hippocampal CA1 Pyramidal Neurons during Orthodromic Stimulation.

The study examined the effect of calcium salt of N-(5-hydroxynicotinoil)-L-glutamic acid (Ampasse preparation) on neuronal activity in hippocampal CA1 area evoked by stimulation of Schaffer collaterals at a rate of 1 Hz (30 impulses during 30 sec) in the surviving hippocampal slices of Wistar rats. The records of 1st and 30th orthodromic population spikes showed that Ampasse in concentrations of 500 μM, 1, 2, and 10 mM facilitated the synaptic transmission in Schaffer collaterals - hippocampal CA1 pyramidal neurons axis; the maximum effect was observed at 2 mM Ampasse. When used in a concentration of 10 mM, Ampasse provoked epileptiform activity, which could be prevented by MK-801, a specific noncompetitive antagonist of the NMDA-receptor complex.

Antidiabetic Properties of Low-Molecular-Weight BDNF Mimetics Depend on the Type of Activation of Post-Receptor Signaling Pathways.

Reduced proliferation and enhanced apoptosis of β cells in diabetes mellitus are associated with a deficiency of brain-derived neurotrophic factor (BDNF). Low-molecular weight compounds similar to different BDNF loops were synthesized at the V. V.

Pro/Antigenotoxic Activity of Usnic Acid Enantiomers In Vitro.

The effect of usnic acid enantiomers on the genotoxic effects of dioxidine and methyl methanesulfonate was studied in vitro in human peripheral blood lymphocytes by the DNA comet method. We found that usnic acid enantiomers in a concentration range of 0.01-1.

Comparison of the Pharmacological Effects of Dimeric Dipeptide Nerve Growth Factor Mimetic GK-2 and Mexidol on the Model of Ischemic Stroke in Rats.

We compared the effects of GK-2 (dimeric dipeptide mimetic of nerve growth factor) and Mexidol (standard preparation for the therapy of stroke) on rat model of transient occlusion of the middle cerebral artery. GK-2 and Mexidol were administered intraperitoneally in the most active doses (1 and 100 mg/kg, respectively) 6 h after surgery and then once a day for 6 days. The preparations reduced the volume of cerebral infarction (by 60 and 30%, respectively).

Non-Competitive NMDA Receptor Antagonist Hemantane Reduces Ethanol Consumption in Long-Term Alcohol Experienced Rats.

Activity of hemantane, an amino adamantane derivative, exhibiting the properties of lowaffinity non-competitive NMDA receptor antagonist, was evaluated in experimental in vivo models of alcoholism. Hemantane had no effects on the formation and manifestation of behavioral sensitization to ethanol in DBA/2 mice. Under conditions of free choice between 10% ethanol and water, hemantane (20 mg/kg/day for 14 days, intraperitoneally) significantly reduced the daily ethanol intake in random-bred male rats with formed alcohol motivation (>4 g/kg of ethanol).

S100A9 Protein Aggregates Boost Hippocampal Glutamate Modifying Monoaminergic Neurochemistry: A Glutamate Antibody Sensitive Outcome on Alzheimer-like Memory Decline.

Alzheimer's disease (AD) involves dementia conceivably arising from integrated inflammatory processes, amyloidogenesis, and neuronal apoptosis. Glutamate can also cause neuronal death via excitotoxicity, and this is similarly implicated in some neurological diseases. The aim was to examine treatment with in vitro generated proinflammatory protein S100A9 aggregate species alone or with glutamate antibodies (Glu-Abs) on Morris water maze (MWM) spatial learning and memory performance in 12 month old mice.

Alcoholic Cardiomyopathy: Translation Model.

We developed a translation model of alcoholic cardiomyopathy in rats. By the end of forced alcoholization (the rats received 10% ethanol solution as the only source of fluid for 24 weeks; mean daily ethanol consumption was 5.0-6.

Activities of Proline-Specific Proteinases in the Serum and Cerebrospinal Fluid of Rats with the Fetal Valproate Syndrome.

In 60-day-old Wistar rats with fetal valproate syndrome, the brain to body weight ratio was higher by 9.4% and activity of dipeptidyl peptidase IV in the serum and cerebrospinal fluid was higher by 18.4 and 40.

Induced Aneugenic Effects in Mouse Oocytes In Vivo.

Aneugenic effects of the chemicals with antitumor activity were studied in mouse oocytes in vivo by cytogenetic analysis. In control mice, no oocytes with numerical chromosome aberrations were found. Colchicine (0.

Dipeptidyl Peptidase 4 Inhibitors Diprotin A and Sitagliptin Administered on Weeks 2-3 of Postnatal Development Modulate Monoamine Metabolism in the Striatum of Adult Rats.

The levels of monoamines and their metabolites in brain structures of adult (3-month-old) rats with emotional and motivational disorders induced by inhibitors of dipeptidyl peptidase 4 (DPP-4; EC 3.4.14.

Delayed Results of Experimental Afobazole Therapy in Rats after Acute Myocardial Infarction.

Delayed cardioprotective effects of anxiolytic Afobazole (15 mg/kg, intraperitoneally for 14 days) were evaluated using dynamic echocardiographic recordings on days 2, 15, 56, and 98 after experimental myocardial infarction modeling (rat model of acute myocardial ischemia). The cardiotropic activity of Afobazole is assumed to be related to its agonistic effects on σ receptor of cardiomyocytes. It was found that animals treated with Afobazole had no signs of heart failure by the end of observation, as evidenced by left ventricular ejection fraction.

Antiangiogenic Effects of Nerve Growth Factor Loop 4 Monomeric Dipeptide Mimetic.

The effects of GK-1, a monomeric dipeptide mimetic of nerve growth factor (NGF) loop 4, on angiogenesis were studied in vitro and in vivo. Experiments on human umbilical vein endothelial cells HUVEC showed that the test compound did not affect tubulogenesis (initial stage of angiogenesis) and prevented realization of the angiogenic effect of NGF and its dimeric dipeptide mimetic GK-2. Experiments on rat hind limb ischemia model demonstrated that GK-1 (1 mg/kg/day intraperitoneally over 14 days) significantly reduced the density of the capillary network in ischemic tissue and increased the number and area of Zenker necrosis in comparison with the control.

Anxiolytic Properties of Trimetazidine in Experimental Models of Increased Anxiety.

Effect of trimetazidine (20 and 30 mg/kg) on elevated plus maze behavior of rodents was assessed in the genetic and pharmacological anxiety models. Single intraperitoneal injection of trimetazidine in a dose of 20 mg/kg prevented anxiety development in highly emotional male BALB/c mice and increased the time spent in open arms of the maze. In outbred male rats receiving 10% ethanol solution for 20 weeks, trimetazidine administered intraperitoneally in a dose of 20 mg/kg for 28 days abolished ethanol withdrawal-induced anxiogenesis developed against the background of 4-week alcohol deprivation: it increased the time spent in open arms, the number of entries into open arms, and total locomotor activity in the maze.

Dipeptide Mimetic of the Brain-derived Neurotrophic Factor Prevents Impairments of Neurogenesis in Stressed Mice.

Brain-derived neurotrophic factor (BDNF) plays the central role in the mechanisms of regulation of neurogenesis and neuroplasticity. Impairment of these mechanisms is considered as one of the main etiological factors of depression. Dimeric dipeptide mimetic of BDNF loop 4 bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide (GSB-106) was synthesized at the V.