Resume. Objective. Current insufficiency in treatment of Parkinson’s disease determines the search for new pharmacological targets to achieve neuroprotection and reduce the severity of motor impairment. It is known that ligand activation of chaperone sigma-1 (SigmaR1) and inhibition of quinone reductase 2 (NQO2) cause cytoprotection. Anxiolytic drug afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) interacts with SigmaR1 and regulatory site of NQO2, inhibiting it. In vivo and in vitro experiments have demonstrated neuroprotective effect of afobazole. However, the effect of afobazole on motor deficit and motion coordination in model of Parkinson’s disease was not studied. Aim. To study the influence of afobazole on latency to fall in rotarod test in mice with induced 6-hydroxydopamine (6-OHDA) Parkinsonism. Methods. Male CD-1 (ICR) mice were tested at accelerated and constant speed rotarod. Afobazole was administered during 14 days (2.5 mg/kg, ip) at course start 30 minutes after unilateral intrastriatal injection of 5 |xg 6-OHDA. Results. Chronic administration of afobazole (2.5 mg/kg) to hemiparkinsonian mice increases their latency to fall 3.9 fold contrary to placebo treated mice in constant speed rotarod. Afobazole negates 6-OHDA in accelerating rotarod increasing latency to fall 1.6 fold as compared to placebo group. Conclusion. Afobazole prevents motor function impairment in hemiparkinsonian mice with 6-OHDA lesion in rotarod test. Observed effect of afobazole can be a result of it neuroprotective properties derived from SigmaR1 and NQO2 interaction.

Myoinositol is the basis for the synthesis of an important group of signal molecules, inositolphosphates, which mediate signal transmission from receptors of growth factors and neurotransmitters. Grants myo-Inositol promote the prevention of folate-resistant defects and neuroprotection of the fetal brain ischemia. The paper presents the results of a study of the effects of myoinositol on the growth of cerebellar neurons in culture under glutamate stress. It is shown that the effects of myoinositol on the survival of neurons (+17 %) exceed the effects of drugs that are usually used for neuroprotection (peptide extracts - + 10 %, choline preparations - no more than 3 %). Confirmed in the present work, a direct neuroprotective effect of myo-Inositol indicates the importance of the use of myo-Inositol during pregnancy with the aim of neuroprotection of the fetal brain.

Resume. Background. Adverse medical and social consequences of alcohol abuse determine the relevance of the search for new targets and methods of effective prevention and treatment of alcoholism. A significant limitation of the use of benzodiazepine anxiolytics in the treatment of alcohol disorders is their ability to potentiate the effects of ethanol. Earlier it was found that the original afobazol, effective in the treatment of anxiety disorders, in the range of anxiolytic doses does not affect the duration of alcoholic sleep and ethanol-induced muscle relaxation. The aim of the present work was to investigate the effects of afobazole on hyperlocomotion and expression of behavioral sensitization induced by ethanol. Methods. The effect of afobazole at the doses 1.0 and 10.0 mg/kg, i.p., on the ethanol-induced hyperlocomotion and behavioral sensitization was assessed in actometer OPTO-VARIMEX in male DBA/2 mice with increased sensitivity to the activating effect of ethanol. Results. Afobazole at a dose of 10.0 mg/kg, but not 1.0 mg/kg after acute administration prevented the development of ethanol-induced (2.0 g/kg, i.p.) hyperlocomotion, like naloxone 1.0 mg/kg, i.p., and antagonized ethanol-induced behavioral sensitization. Conclusion. Thus, the data obtained suggest that afobazole is capable of modeling the motivational effects of ethanol.

Resume. Objective. Inhibition of quinone reductase 2 (NQO2) is a perspective target to achieve neuroprotective effect. Anxiolytic drug afobazole (5-Ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihidrochloride) and its main metabolite M-11 (2-[2-(3-oxomorpholin-4-il)-ethylthio]-5-ethoxybenzimidazole hydrochloride) can interact with melatonin dependent regulatory site of NQO2. Previously we have figured that afobazole inhibits NQO2. However, the role of interaction between M-11 and NQO2 is unclear. Aim. To study the effect of M-11 on activity of NQO2. Methods. The influence of M-11 on activity of human recombinant NQO2 (hNQO2) was measured utilizing fluorescent spectroscopy. Results. M-11 inhibits hNQO2 in concentrations of 0.5 and 1.0 mM, decreasing enzymatic reaction velocity on 12 and 24 % respectively. In same concentrations, M-11 is inferior to afobazole. Conclusion. Compound M-11 inhibits NQO2 and can be used to study pharmacological effects of afobazole caused by interaction with regulatory site of enzyme.

Resume. Previously in the Zakusov Institute of Pharmacology the linear substituted glyproline GZK-111, N-phenylacetyl-glycyl-L-proline ethyl ester, which is capable to convert into the neuropeptide cyclo-prolylglycine (CPG) in biological media and displaying the nootropic, anxiolytic, antihypoxic and neuroprotective activity, was designed and synthesized. The aim of the work was to study the neuroprotective activity of analogues of substituted glyproline GZK-111 at the C- and N-terminus in vitro on the oxidative stress model in comparison to the GPG. Oxidative stress caused by H₂O₂ (1.5 mM) led to significant decrease in the hippocampal cells HT-22 viability. L-CPG protected cells against H₂O₂ in concentrations up to 10^-7M when applied both 24 h before and immediately after damage. The compound with an open carboxylic group (GZK-115) like CPG protected HT-22 cells from death in both experimental schemes at concentrations up to 10^-7M. The substituted amide GZK-119 added 24 h before cell damage, had a cytoprotective effect at a concentration of 10^-7M, and after peroxide damage in concentrations of 10^-6 - 10^-7M. The D-enantiomer of ethyl ester N-phenylacetyl-glycyl-proline (GZK-121) and the compound with the extension of the N-acyl fragment to the CH₂-group (GZK-45) were effective at concentrations up to 10^-6M in both experimental schemes. Simultaneous extension of the N-acyl fragment to the CH₂ group and replacement of the ester with an amide (GZK-50) resulted to protection of the cells from death only after H₂O₂. Thus, it was established that all investigated substituted glyprolines possessed neuroprotective activity in experiments in vitro under conditions of oxidative stress in HT-22 cells. The most active compounds were GZK-119 and GZK-115.

Resume. The purpose of this study was to compare neuroprotective properties of the dimeric dipeptide mimetics of the 1^st, 2^nd and 4^th Loops of BDNF - GSB-214 (heptamethylenediamide bis-monosuccinyl-methionyl-serine), GTS-201 (hexamethylenediamide bis-hexanoyl-seryl-lysine) and GSB-106 (hexamethylenediamide bis-monosuccinyl-seryl-lysine) in the HT-22 hippocampal cells in conditions of oxidative stress. It has been established that the mimetic of the 4^th loop of BDNF shows a neuroprotective effect in lower concentrations compared to mimetics based on the 1^st and 2^nd loops when applied 24 hours before and immediately after the damages.

Resume. The effect of subchronic administration of nootropic drugs of different structures (piracetam 200 mg/kg/day, pantocalcin 200 mg/kg/day, semax 0.6 mg/ kg/day, nooglutil 50 mg/kg/day) to mice of the outbred line 1CR on spontaneous research activity in a closed cross-maze and on the binding characteristics of 5-HT_2A-receptors in striatal membranes. In experiments using [³H] (+)Ketanserin, it has been established that the mice brains exhibiting a low efficacy of exploratory behavior (LEEB) in the closed cross-maze test has a lower density of 5-HT_2A receptors (B_max = 519 ± 13 fmol/ mg , p = 0.02) in comparison with the subpopulation with high efficacy of exploratory behavior (HEEB) (639 ± 48 fmol / mg). After 5-fold administration of nootropics, only in groups with LEEB there was a significant increase in the Bmax value under the action of all investigated nootropics: piracetam (643 ± 42 fmol/mg); pantocalcine (662 ± 29 fmol/mg); semax (742 ± 29 fmol/mg) and nooglutil (1145 fmol/mg) at p = 0.01. By the Kd value, the subpopulations did not initially differ and did not undergo significant changes under the action of the drugs. The presence of serotonin-positive effects of all drugs studied in animals with initially reduced receptor density is consistent with the hypothesis of the selective, modulating nature of the nootropics action.

Resume. The objective of this study is to evaluate pharmacokinetic parameters of tritium-labeled cycloprolylglycine [³H] -CPG following intravenous bolus administration of 5.7 μg (2 mCi). [³H] -CPG was prepared by solid-state catalytic isotopic exchange with spillover-tritium. It was found that plasma concentration-time profile of [³H] -CPG is adequately fit by a two-compartment model. The pharmacokinetic parameter estimates revealed rapid а-phase (distribution phase) (T_1/2α min) followed by a slower β-phase of elimination (T_1/2β 80 min). These findings are consistent with previous results of pharmacokinetic study of CPG as a noopept metabolite. CPG is differ significantly from other therapeutic peptides in pharmacokinetic profile (T_1/2 , MRT, etc), which implies that CPG has a more prolonged duration of action.

In the group of healthy volunteers (women 24-53 years, n = 12) pharmacokinetic curves of levels 25(OH)D and 1,25(OH)D in the blood for two dosage forms of oil solution - the drug Vigantol (n = 6) and chewing tablets - Ultra-D (n = 6) were obtained. Each drug was taken once in a dose of 10,000 IU, then blood sampling was carried out for 6 hours. The multichamber and tubeless pharmacokinetic analysis of the collected data was carried out. It was found that both drugs are characterized by comparable indicators of pharmacokinetics. For example, for the Ultra-D tubeless analysis allowed us to estimate the values of C_max = 28 ± 4 ng/ml, t_max = 50 ± 15 min, C_last = 20 ± 1 ng/ml, for other uses = 8586 ± 693 ng/ml*min, MRT_t = 170 ± 4 min, L_z = 0.00087 ± 0.0004 inch rnin-1, T_1/2 = 15.5 ± 7.2 h, C_L = 7 ± 2 ml/min, V_d = 9.04 ± 1.24 L. Thus, after taking chewable tablets, the area under the curve (indicator for other uses) characterizing the bioavailability, was significantly higher. This is due to the fact that the components of saliva accelerate absorption, since the solubilization of molecules of cholecalciferol begins already in the oral cavity. The pharmacokinetic parameters obtained were practically independent of the age of the volunteers. At the same time, significant correlations of pharmacokinetic parameters with initial levels of 25(OH)D in blood were established. Multi-chamber pharmacokinetic analysis showed that the obtained pharmacokinetic curves with a high degree of confidence correspond to the multi-chamber model, which includes three compartments: "GI", "Central blood circulation" and "depot 25(OH)D".