Correction of Alcohol-Induced Damage to Mitochondria in Cardiac and Cerebral Cells by Derivatives of Neuroactive Amino Acids.

We studied LPO intensity and respiration of mitochondria in brain and heart cells of rats receiving 5% ethanol for 20 weeks and treated with derivatives of neuroactive amino acids. Chronic semicompulsory alcohol intoxication increased the concentration of LPO products in cardiac and cerebral mitochondria by 46 and 45% (diene conjugates), by 97 and 8% (diketones), and by 28 and 81% (malondialdehyde), respectively, reduced activity of antioxidant enzymes in cardiac and cerebral mitochondria by 24 and 45% (glutathione peroxidase) and by 22 and 26% (superoxide dismutase), respectively, and uncoupled the process of respiration and ATP synthesis, which manifested in a decrease in respiratory control (V3/V4 ratio according to Chance). Glutamic acid derivative Neuroglutam (26 mg/kg) and GABA derivative succicard (44 mg/kg) administered intraperitoneally daily for 28 days after termination of alcoholization decreased the levels of primary and secondary LPO products, up-regulated activity of antioxidant enzymes in mitochondria of the heart and brain, and moderated the mitochondrial dysfunction.

[Age-specific changes in the functional indices of rats' cardiac mitochondria in chronic alcohol intoxication.]

The effect of chromic continuous consumption of 5 and 10% ethyl alcohol over 6 months on the respiratory function and oxidant/antioxidant status of rats' cardiac mitochondria of different gender and age has been studied. A decrease in oxygen consumption rate by cardiomyocyte mitochondria in the metabolic conditions V2, V3, V4 according to Chance involving activation of respiratory chain complexes I, I+II and II in elderly (24-month old) animals as compared to young (11-month old) animals. As the rats were ageing, the concentration of lipid peroxidation (LPO) products (malondialdehyde) was increasing, while the activity of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) was decreasing in cardiomyocyte mitochondria. Chronic alcoholization of 24-month old rats of both genders resulted in a more pronounced decline in the respiratory function activity of cardiac mitochondria, uncoupling of respiration and oxidative phosporylation, reduced activity of antiradical protection enzymes and increased LPO products as compared to younger rats.

Comparison of the Efficiency of Adeprophen and Antidepressants of Various Groups on the Model of Reserpine-Induced Depression in Rats.

A new (aryloxyalkyl)adenine derivative Adeprophen (9-[2-(4-isopropylphenoxy)ethyl]adenine, VMA-99-82) has a strong antidepressant effect on the model of reserpine-induced depression in rats (single dose 4 mg/kg, intraperitoneally). This effect manifested in suppression of depression-like behavior in the Porsolt forced swimming test (shortening of immobility time and increase in immobility latency, number of jumping episodes, and time of active swimming) and sucrose consumption/preference test (increase in the consumption of 20% sucrose solution in g/100 g body weight and percentage of sucrose preference in relation to the total fluid preference). Adeprophen had a greater antidepressant effect than sertraline and fluoxetine, but was less potent than amitriptyline, imipramine, venlafaxine, and to a lesser extent to paroxetine.

Comparison of Nootropic and Neuroprotective Features of Aryl-Substituted Analogs of Gamma-Aminobutyric Acid.

GABA analogs containing phenyl (phenibut) or para-chlorophenyl (baclofen) substituents demonstrated nootropic activity in a dose of 20 mg/kg: they improved passive avoidance conditioning, decelerated its natural extinction, and exerted antiamnestic effect on the models of amnesia provoked by scopolamine or electroshock. Tolyl-containing GABA analog (tolibut, 20 mg/kg) exhibited antiamnestic activity only on the model of electroshock-induced amnesia. Baclofen and, to a lesser extent, tolibut alleviated seizures provoked by electroshock, i.e. both agents exerted anticonvulsant effect. All examined GABA aryl derivatives demonstrated neuroprotective properties on the maximum electroshock model: they shortened the duration of coma and shortened the period of spontaneous motor activity recovery. In addition, these agents decreased the severity of passive avoidance amnesia and behavioral deficit in the open field test in rats exposed to electroshock. The greatest neuroprotective properties were exhibited by phenyl-containing GABA analog phenibut.

Effects of Phenibut and Citrocard on Non-Competitive and Competitive Behavior during Provoked Aggression in Animals.

Anti-aggressive effects of phenibut (25 mg/kg) and its structural analogue citrocard (50 mg/kg) were revealed in rats under condition of provoked intraspecific aggression. These substances significantly decreased manifestations of aggression in animals: they increased the latency of attacks and reduced their number. Anti-aggressive effects of citrocard were more pronounced than effects of phenibut under conditions of non-competitive aggression induced by fear of inescapable painful exposure or under conditions of competitive aggression reflecting the ability of animals to reveal adaptive social communicative skills in aversive situation.

Dose-dependent effects of ß-phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) on animal behavior.

ß-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) in doses of 13-650 mg/kg suppressed depressive behavior of animals in the Porsolt test (i.e. produced antidepressant properties), reduced anxiety in the open-field, elevated plus maze, and Vogel conflict tests (i.e. produced anxiolytic effects). RGPU-135 in doses of 26-130 mg/kg exhibited more pronounced antidepressant action and in doses of 26 and 52 mg/kg had more pronounced anxiolytic effects. RGPU-135 in doses of 13-78 mg/kg increased locomotor and exploratory activity of animals in the open-field test. Activating effects of this agent decreased with increasing the dose. RGPU-135 in the subtoxic dose (650 mg/kg) suppressed locomotor activity of animals (produced sedative effect).

Changes in intracellular potentials of snail neurons induced by ß-phenylglutamic acid hydrochloride.

ß-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutamine, or glutarone) in concentrations of 1, 10, 100, and 1000 µM reversibly and dose-dependently modulated the intracellular action potentials in Plantorbarius corneus snail neurons and hyperpolarized the membrane by 9.1±2.5% with maximum shift of resting potential at 100 µM. Hyperpolarization was accompanied by up-regulation of synaptic activity and changes in the pattern of impulse activity manifested by a decrease in the discharge rate, shortening of the interburst time, increase in the mean number of spikes in the bursts, and shortening of the interspike time within the bursts. Both hyperpolarization and impulse activity rearrangement persisted for 10-20 min after washing of RGPU-135.

Comparison of neurotropic effects of L-glutamic acid and its new derivative ß-phenylglutamic acid hydrochloride (RGPU-135, glutarone).

In contrast to L-glutamic acid (200 mg/kg), ß-phenylglutamic acid hydrochloride (26 mg/kg) produces no anticonvulsant effects during generalized convulsions induced by "maximum electric shock". However, ß-phenylglutamic acid hydrochloride was more potent than L-glutamic acid in increasing survival rate, promoting recovery of spontaneous motor activity, and maintainance locomotor and exploratory activity in the open field test and cognitive functions in conditioned passive avoidance test, i.e. exhibited neuroprotective activity. This substance did not change the threshold of pain induced by electric stimulation of paws (up to vocalization) and thermal tail stimulation (tail-flick), whereas L-glutamic acid decreased this parameter. ß-Phenylglutamic acid suppressed aggression in the test for provoked unmotivated aggression, while L-glutamic acid enhanced it. Due to these neurotropic effects, ß-phenylglutamic acid hydrochloride can be used as the basis for the development of drugs with antidepressant, anxiolytic, and neuroprotective actions.

[Antidepressant properties of beta-phenylglutamic acid hydrochloride (RGPU-135, glutarone) in comparison to imipramine, tianeptine, and fluoxetine].

The new glutamic acid derivative--beta-phenylglutamic acid hydrochloride (RGPU-135, glutarone) (in a dose of 26 mg/kg), imipramine (15 mg/kg), tianeptine (2.5 mg/kg) and fluoxetine (20 mg/kg), show antidepressant action in the tail suspension test and Porsolt swim test. All these drugs cause reduction in the intensity of depressive behavior and lead to increase in the rate of active behavior of avoidance of aversive situation with animals. The RGPU-135 compound shows antidepressant activity equal to that of imipramine, which is statistically significantly more pronounced than that of fluoxetine and tianeptine.

[Depressive state of rats in conditions of chronic combined stress caused by the combination of differently modal stressors].

Chronic combined stress with the change of differently modal stressors (noise, vibration and pulsating bright light) according to the stochastic scheme against the background of constant stressors (restriction of movement, fluctuations of the temperature of the environment) causes symptoms of depression-like animal behavior, having the pronounced phenomenological simila rity with the clinical presentation of depression: anxiety, behavioral correlates of despair, hypodynamia, anhedonia, as well as morphosomatic consequences of chronic stress: involution of the thymus and spleen, hypertrophy of epinephros, ulceration of the mucous stomach membrane. Imipramine and fluoxetine effectively reduce the stated behavioral disorders, their effectiveness corresponds to the results of clinical studies and the data received from other models of depression. The described model of depression, has satisfactory, corresponding, constructive and predictive validity and can be used for physiological, ethological, and pharmacological studies.

[Some aspects of the psychostimulant effect of a phenyl derivative of glutamic acid (RGPU-135, glutarone) in experimental animals].

Hydrochloride of beta-phenylglutamic acid (RGPU-135, glutarone, neuroglutamine) administered in dosis 13 mg/kg and 26 mg/kg doses increases exercise performance of outbred mice in repeated forced dynamic load test, reduces the intensity of fatigue, and accelerates adaptation to loading. In contrast, beta-phenylethylamine (20 mg/kg) under the same conditions decreases the exercise performance and adaptation capacity and accelerates the development of fatigue. The RGPU-135 compound, similar to typical psychostimulants, in a dose of 26 mg/kg increases the spontaneous motion activity of inbred C57BL/6 mice with the active phenotype of stress response, but not in the BALB/c line mice with the passive phenotype. The RGPU-135 exhibits a psychostimulant activity without an "exhaustive" effect characteristic of psychostimulants.

Functional aspects of neuroprotective effects of new salts and compositions of baclofen in the convulsive syndrome caused by electroshock.

New salts of baclofen (4-amino-3-(para-chlorophenyl)-butyric acid) and its compositions with organic carbonic acids (citric, succinic, malic, oxalic, nicotinic, glutamic acids and glycine) exhibited neuroprotective and anticonvulsive effects. They reduced the intensity of the convulsive syndrome and postconvulsive psychoneurological disorders in animals exposed to the maximum electroshock and electroconvulsive shock. Analogs of baclofen containing citrate and to a lesser extent those containing glutamate and glycine were significantly more active than the initial substance.

[Fenibut and its citrate prevent psychoneurological disorders caused by chronic stress (paradoxical sleep deprivation)].

The antistress protective action of two structural analogs of GABA, fenibut and its salt with citric acid (fenibut citrate, citrocard, RGPU-147), has been studied using a model of chronic stress caused by seven-fold 24-h deprivation of paradoxical sleep phase at an interval of 24 h between the deprivations. It is established that fenibut and fenibut citrate produce a protective action by (i) reducing the intensity of emotional disorders in the open-field test and elevated plus maze test, (ii) decreasing cognitive disorders in the tests for conditioned avoidance response and extrapolatory deliverance; and (iii) limiting stress reaction due to a decrease in the intensity of adrenal hypertrophy, thymus involution, and stomach mucous membrane ulceration. Fenibut citrate surpasses fenibut in the intensity of antistress protective action.

[The new glutamic acid derivative RGPU-135 (glutaron, neuroglutamin) modulates ion currents in mollusk neurons].

The new glutamic acid derivative RGPU-135 (3-phenylglutamic acid hydrochloride, glutaron, neuroglutamin) produces dose-dependent and reversible modulation of transmembrane sodium, potassium and, to a greater extent, calcium ion currents in neurons of Lymnaea stagnalis and Planorbarius corneus mollusks at concentrations of 1, 10, 100, and 1000 microM. At concentrations within 1 - 10 microM micromole, Ca and K currents are activated rather insignificantly; at 100 pmole, the amplitude of calcium currents is increased by 5 - 10%; and at 1000 microM, the Na and K ion currents are suppressed by 5 - 12%. RGPU-135 does not influence the membrane surface charge potential and the gating of ion channels. The effects of RGPU-135 were quickly reversible, which indicated the relatively weak drug binding to the membrane structures and ion channels.

[Anxiosedative properties of heteryl(aryl)-containing hexahydrobenzofuranon derivatives].

The anxiosedative properties of 2-hydroxyimino-3-indolylyl(aryl)-4-oxo-2,3,4,5,6,7-hexahydrobenzofuranon derivatives have been studied using the open-field test, elevated plus-maze test, and conflict drinking procedure as developed by Vogel. It is established that all derivatives with both indole and aryl substituents produce a sedative effect. However, an anxiolytic effect is determined by the presence of indole substituent in the third position of the hexahydrobenzofuran molecule.

[Psychotropic effect of phenibut salts and their compositions with organic acids].

The spectra of psychotropic action of some phenibut salts (succunate, maleate, nicotinate) and a composition of phenibut with glutamic acid were studied. It is established, that the substances studied show psychotropic activity spectrum generally similar to that of phenibut, but different in expressiveness of some particular effects. Compound RSPU-149 exhibited the most pronounced psychotropic action: its anxiolytic effect was below, the antidepressant effect was comparable with, and the nootrope action exceeded that of phenibut.

[Gender differences in action Fenotropil and its structural analog--compound RGPU-95 on anxiety-depressive behavior animals].

Fenotropil and its structural analog--compound RGPU-95 to a greater extent reduce the severity of anxious and depressive behavior in male rats than in females. On expression of the anxiolytic compound RGPU-95 significantly exceeds Fenotropil, but inferior to Diazepam; of antidepressant activity--comparable to Melipramin and exceeds Fenotropil.