[The efficacy of human NGF dipeptide mimetic on the streptozotocin-induced model of diabetes in rats].

The effect of a new dimeric dipeptide mimetic GK-2 of the loop-4 human NGF (hexamethylendiamide-bis-N-monosuccinyl-glycil-L-lysine) was investigated for the first time on the dynamics of hyperglycemia and body weight loss caused in Wistar rats by streptozotocin (45 mg/kg i.p.) Prophylactic (2 weeks before streptozotocin) daily administration combined with therapeutic (4 weeks after STZ) administration of GK-2 (0.1 mg/kg i.p.) was shown to attenuate significantly the degree of hyperglycemia and to reverse the streptozotocin-induced weight loss.

[In vivo study of the pharmacokinetic interaction of afobazole and losartan (cytochrome CYP2C9 substrate)].

The influence of afobazole on isoenzyme CYP2C9 production in rats was studied using losartan as the marker drug. Single dose of losartan was administered orally without afobazole in a dose of 30 mg/kg and in the same single (30 mg/kg) on the background of 3- and 4-day administration of afobazole in a dose of 5, 25, 75, 100, and 125 mg/kg. At 5 mg/kg (effective dose for anxiolytic effect), afobazole did not cause any induction/inhibition effect on CYP2C9 isoenzyme. A multiple increase in afobazole dose was manifested by a moderate induction effect. The maximum induction effect of afobazole was achieved in a dose of 75 mg/kg. At doses above 75 mg/kg, the induction effect of afobazole was less pronounced.

[Neuroprotective effects of a dipeptide mimetic on the GK-2 nerve growth factor in model of permanent common carotid artery occlusion in rats].

The behavioral and biochemical effects of a new dipeptide mimetic of the GK-2 nerve growth factor (NGF) have been studied on a model of chronic cerebral ischemia induced by permanent common carotid artery occlusion in rats. It is established that subchronic intraperitoneal injections of GK-2 (0.5 mg/kg) 4 h after surgery, followed by seven more injections made every 24 h, fully prevent the death of operated animals and reduces the development of habitation deficit (open-field test) and decrease in exploratory activity (novel object examination) two weeks after surgery, as well as fully restores the viability of cerebral cortex cells and decreases the hyperexpression of HSP70 in cerebral cortex.

[The search of small molecules with antipsychotic activity on the background of neurotensin].

Tridecapeptide neurotensin (NT) is known to exert the neuroleptic-like effects in case of its intracerebral administration. The group of systemically active dipeptides , acylprolyltyrosines, was constructed on the background of NT. Methyl ester of N-caproyl-L-prolyl-L-tyrosine (Dilept) was chosen for further development. The paper is dealing with main principles of Dilept'design and with analysis of the experimental data concerning its effect on the "translational" model of schizophrenia--the deficit of prepulse inhibition of the acoustic startle-reaction caused by either dopamine-mimetic, apomorphine, or by the uncompetitive NMDA-blocker, ketamine. Dilept was shown to attenuate these deficits both in case ofintraperitoneal and peroral administration. Dilept is considered as a potential antipsychotic.

[Effects of afobazole on the BDNF content in brain structures of inbred mice with different phenotypes of emotional stress reaction].

Changes in the BDNF content in brain structures--hippocampus, hypothalamus, striatum, and frontal cortex--were determined in mice of different emotional-stress reaction phenotypes, which were subjected to emotional stress and treated by the selective anxiolytic afobazole. The changes were different in BALB/c and C57BL/6 mice. Afobazole exhibited a significant protector action against a decrease in the brain BDNF level caused by emotional stress in BALB/c mice.

[Interaction of tropoxin and its molecular fragments tropan and 3,4,5-trimethoxybenzoate with serotonin receptors of cortical neurons in the rat brain (a microionophoretic study)].

The effects of the antimigraine drug tropoxin and its main molecular fragments - tropan and 3,4,5-trimetoxybenzoate (TMB) - on the serotonin sensitivity of postsynaptic neuronal membrane in rat brain sensorimotor area has been studied using a microionophoretic (MIP) technique. All the three substances significantly reduce the excitatory neuronal response to serotonin, which is manifested by an increase in the rate of the spontaneous action potentials. With respect to the antiserotonin effect, the substances can be arranged in the following order: tropoxin > tropan > TMB. The sum of the effects of tropan and TMB (for both simultaneous and separate action upon the target cells) was significantly lower than the effect of tropoxin in all doses (MIP currents). It is concluded that a pronounced antiserotonin effect of tropoxin is produced only provided that the entire molecular configuration is retained. Tropan and TMB, being tropoxin metabolites, are probably capable of prolonging the antimigraine action upon the decay of tropoxin in the organism. A relationship between the structure and action of serotonin receptor blockers of the tropan series is discussed.

[Dilept: a tripeptoid neurotensin analog combining neuroleptic activity with positive mnemotropic action].

The effect of N-caproyl-L-prolyl-L-tyrosine methyl ester (GZR-123, Dilept), a new antipsychotic drug with a dipeptide structure, on cognitive functions was studied using the passive avoidance conditioned reflex (PACR) test. It was found that the drug improved both the acquisition and retrieval of PACR under the conditions of undertraining and prevented the amnesic effect of transcorneal electroshock. The neurotransmitter analysis of these effects using the corresponding blockers showed the ability of dilept to facilitate the central glutamatergic (NMDA type) and cholinergic (of both muscarine and nicotine types) neurotransmission. No evidence of the involvement of the GABAergic system was observed. The experimental data on the combination of antipsychotic effect with memory improving activity suggests that dilept may be effective in cases of negative symptoms of schizophrenia and psychotic manifestations in Alzheimer disease.

[Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon].

The role of GABAergic mechanisms in realization of the effects of afobazole and picamilon on the cerebral circulation was studied in rats. It is found that the cerebrovascular effect of afobazole significantly decreases on the background of the GABA receptor antagonists bicuculline and picrotoxin. This is evidence of an important role of the GABA system in the its cerebrovascular and neuroprotective activity of afobazole. The results of experiments with picamilon showed that the cerebrovascular effect of this drug is not affected by receptor blocking with bicucullin. However, the blocking of chloride channels of the GABA receptors by picrotoxin significantly decreased the effect of picamilon on the cerebral blood flow.

[Afobazole increases cerebral blood flow in rats with global brain ischemia]. / Usilenie krovosnabzheniia ishemizirovannogo mozga pod vliianiem Abofazola.

The selective anxiolytic drug afobazole administered in a dose of 5 mg/kg increased the cerebral blood flow in rats. The effect was more pronounced in rats with global reversible cerebral ischemia than in intact animals. The ischemia model was caused by occlusion of both common carotid arteries for 120 min with simultaneous reduction of the arterial pressure to 40-50 mm Hg through blood-letting. Afobazole also significantly increased the survival of rats with cerebral ischemia model caused by ligation of both common carotid arteries, which was evidence of the neuroprotector activity. Apparently, the ability of afobazole to improve the cerebral blood flow in ischemized rat brain is an important factor in realization of the neuroprotector activity.

[The effect of ladasten on the activation-induced expression of Fas receptor on T-lymphocytes and their sensitivity to Fas-induced apoptosis]. / Vliianie Ladastena na aktivatsionno-indutsirovannuiu ékspressiiu Fas-retseptora na T-limfotsitakh i ikh chustvitel'nost' k Fas-indutsirovannomu apoptozu.

The effects of ladasten on the activation-induced expression of Fas-receptor on T-lymphocytes, their sensitivity to Fas-induced apoptosis, and the expression of mitogen-activated ERKI/ERK2 protein kinases have been studied. In the range of concentrations 0.1-10 microM, ladasten exhibited a comitogenic effect on the TCR-mediated stimulation of T-lymhocytes ion the peripheral human blood, which was accompanied by an increase in the level of phosphorylated form of ERK-2. At the same time, ladasten virtually did not change the activation-induced expression of Fas-receptor on T-lymphocytes, but reduced the rate of the Fas-induced apoptosis. It was concluded that the immunoprotective effect of ladasten is probably based on a decrease in the rate of Fas-induced apoptosis.

[Multiparametric analysis of the effect of ethanol in various doses on EEG in rats]. / Vliianie étanola vrazlichykh dozakh na éég krys. Mnogoparametricheskii analiz.

Multiparametric EEG analysis (840 parameters) was performed for 24 points over the entire dorsal cerebral cortex in outbred rats intraperitoneally injected with ethanol in low (0.75 g/kg), medium (2.0 g/kg), and high subnarcotic (4.5 g/kg) doses. Acute intoxication with low ethanol doses led to an increase in the spectral power and coherence in the frequency band of the dominating theta-rhythm peak (5.75-7.25 Hz), which was indicative of activation of the septo-hippocampal system (with improvement of the related functions such as attention, memory, and exploratory activity). The coherence was also increased in several high-frequency bands of the EEG alpha- and beta-rhythm. Ethanol administered in medium and high doses produced a shift of the dominating theta-rhythm peak to lower frequencies (4.50-5.75 Hz), which was evidence of reduced activity of the septo-hippocampal system and the related CNS functions. These doses of ethanol significantly decreased the spectral power and coherence in most of the high-frequency bands of the EEG alpha- and beta-rhythm, which can be explained by reduced energy and synaptic activity of the cortex leading to impaired high brain functions and the development of somnolent and narcotic effects. Using special sets of reliably modified parameters and a special algorithm, it is possible to solve the inverse problem of identifying experiments (EEG fragments) corresponding to low, medium, and high doses of ethanol.

Antimutagenic activity of afobazole in various regimens of treatment.

The influence of a new 2-mercaptobenzimidazole derivative afobazole on cytogenetic effects of dioxidine and cyclophosphamide was studied by counting chromosome aberrations in bone marrow cells of C57Bl/6 mice. Afobazole (1-100 mg/kg perorally) exhibited antimutagenic activity determined by its antioxidant properties. This activity depended on the dose and treatment schedule.