Anxiolytic and Antidepressant Effects of Divaza and Brizantin.

The anxiolytic and antidepressant activities of complex preparations divaza and brizantin containing antibodies to brain-specific protein S100 were estimated using Vogel conflict test and Nomura forced swimming test. Course treatment (5 days) of brizantin in a dose of 2.5 ml/kg and divaza in a dose of 7.5 ml/kg significantly increased punished drinking in the Vogel conflict test in comparison with the control. Both drugs also improved general emotional behavior during training prior to the test procedure. Brizantin and divaza in a dose of 7.5 ml/kg increased the number of wheel revolutions in the Nomura forced swimming test in comparison with the control; the effect of divaza was more pronounced. High correlation coefficients between the number of wheel revolutions during the first and second 5-min sessions are also indicative of antidepressant action of divaza and brizantin.

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF.

A large amount of clinical and experimental data suggest the involvement of neurotrophins, in particular the brain-derived neurotrophic factor (BDNF), in depression pathogenesis. However, the therapeutic use of BDNF is limited because of its instability in biological fluids, poor blood-brain barrier (BBB) permeability, and the presence of side effects. A low-molecular-weight mimetic GSB-106, which is a substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized based on the BDNF fourth loop structure at the V.V. Zakusov Institute of Pharmacology (RAMS). GSB-106 was found to exhibit an antidepressant activity in various models of depressive-like state when administered intraperitoneally to outbred mice and rats. An effect for the substance, when administered daily for 4-5 days, was detected in the Porsolt forced swimming test (0.1 and 1.0 mg/kg) and in the tail suspension test in mice (1.0 and 1.5 mg/ kg). An effect for GSB-106 at doses of 0.1 and 0.5 mg/kg was observed after a single application in experiments on rats in the Nomura water wheel test. The obtained evidence supports the hypothesis on the involvement of BDNF in the pathogenesis of various depression conditions, thus opening prospects for searching for new original antidepressants.

[Behavioral and neurochemical aspects of the antidepressive action of GSB-106 dipeptide BDNF fragment].

The behavioral and neurochemical effects of synthetic dipeptide fragment GSB-106 of BDNF, administered in a single dose of 0.1 mg/kg (i.p.), have been studied in comparison to amitriptyline (10 mg/kg, i.p.) on the Nomura depressive state model employing forced-rotating-wheel swim test (FST) in Wistar rats. Amitriptyline is known to increase both the number of wheel turns and the index of correlation between the number of turns in the first and last 5-min intervals of observation. It is established that GSB-6 produces a pronounced antidepressant effect comparable to that of amitriptyline, while not influencing the content of monoamines in brain structures of intact (non-depressive) rats. HPLC study showed that GSB-106 increased the complex parameters of dopamine metabolism (DOPAC/DA and HVA/DA) in nucleus accumbens and striatum of rats undergoing FST as compared to the same indices in intact animals. A decrease in the norepinephrine (NE) content by 50% was detected in striatum and hippocampus of rats with depression model. GSB-106 to significantly increased the number of wheel turnings and prevent the elevation of DA and its metabolite DOPAC levels in hypothalamus. A decrease in 5-HIAA (serotonin metabolite) content was also detected in frontal cortex and hypothalamus.

Anxiolytic activity of tenoten and diazepam depends on conditions in Vogel conflict test.

We compared two modifications of Vogel conflict test and assessed anxyolitic activity of two drugs: diazepam (benzodiazepine anxiolitic) and tenoten (ultra-low doses of antibodies to S-100 protein) in both modifications of the test. It was found that the intensity of anxiolitic effect of the drugs depends on the conditions of Vogel test.

[Effects of amitriptyline, fluoxetine, and tianeptine on the content of monoamines and their metabolites in Wistar rat brain structures].

The effects of antidepressant drugs belonging to different pharmacological groups--amitriptyline, fluoxetine (prozac), and tianeptine (coaxyl)--on the content of monoamines and their metabolites in Wistar rat brain structures (frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocamp) has been studied using HPLC with electrochemical detection. Tricyclic antidepressant amitriptyline (10 mg/kg) was found to produce a moderate increase in the DOPAC/dopamine turnover index in nucleus accumbens, but did not influence the levels of serotonin (5-HT), dopamine, and its metabolites (5-HIAA, DOPAC, and HVA) in other brain structures studied (frontal cortex, hypothalamus, striatum, hippocamp). Fluoxetine (Prozac) (20 mg/kg) decreased both the 5-HIAA content and the 5-HIAA/5-HT (5-HT turnover index) in all brain structures of Wistar rats. In contrast, the effects of Prozac on the level of catecholamines and their metabolites in various brain regions was more complex. Tianeptine (Coaxyl) was demonstrated to increase both the 5-HIAA content and the 5-HIAA/5-HT ratio in all the structures studied (except for nucleus accumbens), in good agreement with the hypothesis concerning a two-phase mode of tianeptine action with enhanced 5-HT secretion in the synaptic gap in the first stage of pharmacological response.

[A drug with the broad spectrum of pharmacological activity for the treatment of complex neuropsychic disorders].

The influence of a pyrrolo-pyrazine derivative AL-613 (synthesized at the Zakusov Institute of Pharmacology) on the behavior of outbred male albino rats has been studied on various experimental models. It was established that AL-613 produces anxiolytic action in a conflict situation model and antidepressant action in forced swim paradigm test, improves active avoidance conditioned reflex acquisition, and increases the amplitude of transcallosal evoked potential. The substance demonstrated properties of anxiolytics, antidepressants, and nootropes. These effects were not accompanied by side effects, which are characteristic of many other drugs of these classes. The preparation exhibit low acute toxicity. It is concluded that AL-613 can be considered as a complex "optimizer" of damaged central nervous system functions.

Comparison of antidepressant effects of azafan, tianeptine, and paroxetine.

Antidepressant activity of Russian product Azafen (pipofezine) and foreign products Paroxetine and Tianepine was compared using behavioral despair test (Porsolt test) and forced swimming test in a container with wheels (Nomura). Azafen significantly shortened the duration of depressive state in both tests. The results suggest that Azafen exhibits pronounced antidepressant activity, superior to that of the reference drugs.

[Antidepressant properties of afobazole in Porsolt and Nomura tests].

Anxiolytic afobazole was shown in the experiments on outbred rats to decrease the immobility in the Porsolt and Nomura swim tests. The degree of afobazole effect in a dose of 5 mg/kg (i.p.) is similar to that of the standard antidepressant amitriptyline administered in doses of 10 mg/kg. Data obtained are testifying to the antidepressant activity of afobazole.

[Effect of phenibut on interhemispheric transmission in the rat brain].

Effects of the nootropic drug phenibut on the transcallosal potential amplitude in the sensomotor brain cortex have been studied in rats. It is established that a single administration of phenibut in a dose of 25 mg/kg (i.p.) increases the transcallosal response amplitude, thus improving the interhemispheric transmission. This effect, being an objective evidence of the nootrope activity, confirms the drug status and corroborates the positive action of phenibut on the learning and memory processes.

Nootropic and antiamnestic effects of tenoten (pediatric formulation) in immature rat pups.

The antiamnestic effects of tenoten (pediatric formulation) was demonstrated on the model of scopolamine-induced amnesia of passive avoidance reflex and the nootropic effect of this preparation was demonstrated on the model of incomplete conditioning and in rat pups with experimental attention deficit syndrome. The efficiency of the preparation was comparable to that of piracetam and phenibut and even surpassed it by some parameters.

Antiaggressive activity of antibodies to S-100 protein in ultralow doses.

Experiments on rats demonstrated antiaggressive activity of ultralow doses of antibodies to S-100 protein in tests of motivated and unmotivated aggression. The effect of ultralow doses of antibodies to S-100 protein in single and course treatment was not inferior to that of benzodiazepine anxiolytic diazepam.

Anxiolytic and antidepressant characteristics of impaza.

Antibodies to endothelial NO synthase in ultralow doses exhibited anxiolytic and antidepressant effects and their efficiency after single and course treatment is not inferior to that of amitriptyline and diazepam. The psychotropic activity of ultralow-dose antibodies to endothelial NO-synthase is presumably one of important mechanisms of their efficiency in the treatment of erectile dysfunction.

Involvement of the GABA-B system in the mechanism of action of ultralow-dose antibodies to S-100 protein.

The involvement of the GABA-B neurotransmitter system in the realization of anxiolytic and antidepressant activities of ultralow-dose antibodies to S-100 protein is demonstrated. Simultaneous injection of ultralow-dose antibodies to S-100 protein and GABA-B receptor agonist baclofen reduced the anxiolytic and antidepressant effects of the drug, while GABA-B receptor antagonist faclofen stimulated the anxiolytic and reduced the antidepressant effect of ultralow-dose antibodies to S-100 protein. The effect of ultralow-dose antibodies to S-100 protein on the GABA-B-ergic system differs from that of benzodiazepine anxiolytics (diazepam) and tricyclic antidepressants (amitryptiline) not affecting this transmitter system.

[Combined action of mexidol and non-narcotic analgesics on pain thresholds and emotional stress behavior in animals].

The influence of non-narcotic analgesics analgin and pentalgin in the basic pharmacological effects of diazepam and mexidol has been studied in outbred male albino rats. It is established that both analgesics do not influence the activity of diazepam. At the same time, they potentiate the analgesic action of mexidol without influencing its antistress action and not inducing any side effects. The strengthening influence of pentalgin was more pronounced. It is concluded that mexidol can be administered in combination with non-narcotic analgesics, in particular with pentalgin, for relieving painful syndrome on the background of stress.

[Comparative study of the effects of amitriptyline, fluoxetine, and tianeptine on the amplitude of transcallosal evoked potentials].

The influence of amitriptyline, fluoxetine and tianeptine upon transcallosal responses has been studied in male albino rats. It is established that amitriptyline does not influence, fluoxetine reduces, and tianeptine increases the amplitude of evoked potentials. These data show evidence that tianeptine facilitates, fluoxetine impairs, and amitriptyline does not affect the interhemispheric transmission.

Study of bipathic effect of phenazepam.

Phenazepam in ultralow doses significantly potentiated anxiolytic and anticonvulsant effects of therapeutic doses of the same drug both after preliminary or simultaneous administration, which attests to bipathic action of phenazepam. The combination of ultralow and therapeutic doses of phenazepam prevented the development of its specific myorelaxant and sedative side effects.

[Mexidol effects in extreme conditions (experiments with animals)].

In extreme conditions like a new situation, bright light, open space, immobilization, height (the open field and lifted cruciform labyrinth test) and a conflict between an unavoidable action and fear of painful mexidol at the doses of 50 and 100 mg/kg of a body weight eliminates anxiety and fear in rats, recovers adequate reactions and the orientative-trying behavior, and lessens aggressiveness. Mexidol extends life span of mice in acute hypoxic conditions. Mexidol is highly competitive with diazepam as an anti-stress agent and excels it as an anti-hypoxic agent; in contrast to diazepam, mexidol does not cause sedation and myorelaxation. Based on these findings, mexidol can be prescribed to humans to maintain efficiency in all kinds of extreme situations.

Involvement of the serotoninergic system in the mechanism of action of ultralow dose antibodies to S-100 protein.

The involvement of the serotoninergic system in the realization of anxiolytic and antidepressant activities of antibodies to S-100 protein in ultralow doses is proven. Administration of ultralow-dose antibodies to S-100 protein in combination with serotoninergic agents (ketanserin and 5-hydroxytryptophan) reduced the anxiolytic and antidepressant effects of antibodies.

[Comparative study of the antidepressant and anxiolytic activity of fluoxetine and tianeptine].

The activity of fluoxetine (prozac) and tianeptine (coaxil) was studied in outbred male rats under Porsolt and S. Nomura modified forced swim tests. The antidepressant effect of tianeptine was much more pronounced that that of fluoxetine. In the conflict situation test, fluoxetine produced anxiogenic action. In contrast, tianeptine decreased (albeit not reliably) the anxiety. In combination with bicuculline (GABAA receptor blocker), the anxiolytic action was more pronounced for both antidepressants, which was manifested by a significant increase in the number of punished water takes. A neural network explaining the observed behavior is proposed, which includes GABA-ergic intemeurons inhibiting serotonin release from serotoninergic terminals.

[Stress-induced alteration of the antiaggressive effect of anxiolytics]. / Izmeneniia antiagressivnogo deistviia anksiolitikov pod vliianiem stresa.

The influence of stresses of various etiology (prolonged isolation, inescapable electrostimulation) on the antiaggressive effect of anxiolytics was studied in outbread white male rats. It was established that, in contrast to the anticonflict effect (decreasing under the action of stress), then antiaggressive action of the drugs studied (diazepam, phenazepam, clonazepam, alprazolam) exhibits qualitative changes. In the absence of stress, the threshold of aggressive reaction is low and anxiolytics increase this level. Under the action of stress, the threshold of aggressive reaction increases, and the same drugs reduce this threshold to the normal level, thus producing proaggressive action. The degree of changes and the rate of restoration of the initial activity depend on the efficacy of anxiolytics, the strength and duration of stress, and on the duration of drug administration during the stress aftereffect. A possible mechanism of this phenomenon can be the interaction of the GABA-benzodiazepine and opiate endogenous systems.