[CHARACTERISTICS OF THE RETINA IN CHRONIC STRESS IN LABORATORY RATS OF DIFFERENT AGE GROUPS].

The retina was studied in albino laboratory male rats of two age groups (12 and 24 months), 10 animals in each subjected to chronic combined stress. The stress was caused in animals by simultaneous exposure to pulsed light, loud sound, swinging and restriction of mobility for 7 days, 30 mm daily. The retina of intact rats of the corresponding age groups (n = 20) served as control. Enucleated eyes of stressed and control animals were processed with standard histological technique and stained with Nissl's method and hematoxylin-eosin. The retina of the stressed animals of both age groups showed the decrease in the number of cells and the disarrangement of its layers, most pronounced in the layers of photoreceptor neurons and ganglion cells. The comparative morphometric analysis demonstrated a reduction of the layer thickness and cell numerical density in the retina of stressed animals, both young (12 months) and old (24 months), as compared to that of control animals.

[Studying the neuroprotective effect of the novel glutamic acid derivative neiroglutam on focal cerebral ischemia in rats].

We have studied the neuroprotective effect of the novel glutamic acid derivative neiroglutam on reversible focal cerebral ischemia in rats. The neuroprotective drug action was assessed by the ability to reduce the severity of neurological deficit (1, 2, 3, 5 and 7 days), forelimb fine-motor disorders (in the ladder test), hind limb motor activity (beam-walking test), and volume of the infarct zone upon 7-day pathologic exposure. It was found that the therapeutic administration of neiroglutam (26 mg/kg, i.p., for 7 days) reduces the volume of necrosis of cerebral tissues in case of focal brain ischemia in animals (on the average by 38%, (p < 0.05) and decreases the severity of motor disorders, which indicates the presence of neuroprotective effect of this compound.

[Neuroprotective effect of neuroglutam under conditions of activated free radical oxidation].

The neuroprotective properties of the novel glutamic acid derivative neiroglutam have been studied in vitro and in vivo. Neiroglutam demonstrated the protective action on 6-OH-dopamine neurotoxicity model in vitro, where free radical oxidation is a basic part of pathogenesis. In control rats, focal brain ischemia caused significant increase in thiobarbituric acid reactive species (TBARS) level and decrease in superoxide dismutase (SOD) enzyme activity. In two-year-old rats, preventive administration of the neiroglutam caused a significant reduction in the TBARS plasma concentration (34.5%, p < 0.05), increased SOD activity, and increased the time of acid-induced hemolysis of erythrocytes (40%, p < 0.05).

[Change of cardiac ino- and chronotropic functions in stressed animals with blockade of different NO-synthases].

AIM: To investigate the effect of long-term immobilization-painful stress on ino- and chronotropic functions of the heart with inhibition of various NO-synthases. MATERIALS AND METHODS: 30 female albino rats were taken. Blockers of NO-system were: aminoguanidine (50 mg/kg), (50 mg/kg) and NG-nitro-L-arginine methyl ester (10 mg/kg). Stress was modeled by suspending the animals for cervical dorsal skin fold for 24 hours. The functional reserves of the heart were studied using adrenoreactivity and isometric load tests. RESULTS: experiments showed that painful stress leads to a decrease of cardiac ino- and chronotropic functions which is observed in the reduction of increment dp/dt+, dp/dt-, LVP and HR during load tests in comparison to control group of intact animals. Selective blockade of nNOS with 7-Nitroindazole causes even greater decrease an increment indices of myocardial contractility and LVP in stressed animals during load tests. The most pronounced inhibition of inotropic function of the stressed animal's heart observed in the non-selective inhibition of NO-synthases by L-NAME. Administration of aminoguanidine to animals (inducible NOS blocker) before and after stress causes an increase of inotropic reserve of the heart, resulting in increased increment of myocardial contractility and relaxation findings, left ventricular pressure and heart rate during load tests, CONCLUSIONS: NO-ergic system plays a significant role in limiting of the negative stress effects on the contractile function of the heart.

[Gravidaprotective action of phenibut in experimental pre-eclampsia].

It was established that the replacement of drinking water by 1.8% NaCl solution in female rats during pregnancy causes experimental pre-eclampsia (EP), as evidenced by an increase in the blood pressure, proteinuria, and edema in the control group as compared to pregnant female rats with normal drinking regime. Animals with EP exhibited disturbance of vasodilating endothelial function, microcirculation disorder, and increased coagulation and thrombogenic potential of blood. In addition, the group with EP showed evidence of the activation of lipid peroxidation (LPO) due to lower activity of antioxidant enzymes. Daily oral administration ofphenibut (25 mg/kg) in female rats with EP during pregnancy prevents the increase in blood pressure and the severity of proteinuria and edemation. Phenibut improves the vasodilator and antithrombotic endothelial functions, increases uterine blood flow, improves microcirculation, limits LPO, and increases the activity of antioxidant enzymes.

[Synthesis, isomery, and hypotensive activity of thiethane-containing ylidenehydrazides of uracilylacetic acid].

Using reaction of hydrazide 2-[6-methyl-1-(thiethane3-yl)uracil-3-yl]acetic acid with arylaldehydes and acetophenone derivatives were obtained acylhydrazones, which exist in DMSO solution as a mixture of two stereoisomers of a E(C=N)-isomer for due to hindered internal rotation around the hydrazide bond. It was revealed that the synthesized compounds exhibit antihypertensive activity.

[Influence of RGPU-207 compound and amiodarone on ion currents in shellfish neurons].

RGPU-207 compound and amiodarone in concentrations of 1, 10, 100 and 1000 microM produce dose-dependent and reversible effects on trans-membrane sodium, calcium, and potassium ion currents of neurons in pond snail and orb snail shellfish. In concentration of 1 microM, both compounds increased the amplitude of potassium ion currents, while not affecting the amplitude of sodium and calcium ion currents. In concentrations of 100 and 1000 microM, dose-dependent suppression of all currents (with predominant potassium ion current suppression) was observed. Under the action of RGPU-207 compound, the kinetics of activation and inactivation of sodium and calcium ion currents was not changed, but the kinetics of activation of the potassium slow current was slowing down. Amiodarone decelerated the inactivation of calcium ion current and accelerated the inactivation of potassium slow current. RGPU-207 compound, in comparison to amiodarone, produces a similar membranotropic effect on the shellfish neurons.

[Alzheimer's disease and geriatric eye diseases in the aspect of amyloid genesis].

Geriatric eye diseases (age-related macular regeneration, pseudoexfoliation syndrome, pseudoexfoliative glaucoma, senile cataract) are one of the most important problems of modern ophthalmology. Meanwhile, the treatment of these diseases continues to be primarily empirically based for lack of not only valid data on their etiology, but even consensus of opinion on their pathogenesis. This review gives the current views on the commonness of the etiopathogenetic and morphological manifestations of Alzheimer's disease and age-related eye diseases in the aspect of amyloid genesis. This approach is a promising attempt to specify the mechanisms responsible for the occurrence and development of neurodegenerative diseases, their markers, and new perspectives in their treatment.

[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.

[Psychomodulating activity of phenotropil in experimental hyperthyroidism].

Psychoimmunomodulating action of phenotropil has been shown on the model of experimental hyperthyroidism. It has been found that the drug (14-days i.p. injection in a dose of 25 mg/kg) is capable of restoring the cellular and humoral immunoreactivity and improve psychoemotonal state of animals by eliminating disturbances in the behavior reactions that appear as a result of the induced hyperthyroidism.

[Hepatoduodenal circulation and excretion of the new GABA derivative citrocard].

Pharmacokinetic investigation of a new gamma-aminobutyric acid (GABA) derivative cirtocard showed that, upon the intravenous introduction, the drug is determined in high concentrations in organs of elimination--the liver and kidneys. The tissue accessibility amounts to 1.341 for the liver and 4.053 for the kidneys and the separation factor is 1.041 for the liver and 4.486 for the kidneys. The study of drug excretion showed that cirtocard is determined in the urine for 48 h, its nephritic clearance being 0.047 L/h and extra-nephritic clearance, 0.33 L/h. For the unchanged substance, a large significance ofhepatoduodenal circulation is low probable, since no more than 1 - 2% of the introduced dose was isolated with bile over entire experiment. It is established that the removal of the unchanged substance does not exceed 10% of the introduced dose. There is high probability of hepatoduodenal circulation and excretion of the preparation in the form of metabolites.

[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.

[Effect of GABA derivative--RSMU-151 on the development of oxidative stress in rats with experimental gestosis].

Experimental gestosis induced in rats by drinking 1.8% sodium chloride solution instead of water during the entire period of pregnancy leads to activation of lipid peroxidation (LPO) process, as manifested by increased concentration of diene conjugates and malonic dialdehyde, decreased concentration of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in homogenates of rat brain, liver, uterus, and placenta. The GABA derivatives--RSMU-151 limits the damaging effect of gestosis, which is manifested by a decrease in the concentration of LPO products and by activation of the antioxidant system enzymes in all organs studied.

[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 reserves of the heart under conditions of alimentary magnesium deficit].

Aim of the study was to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests. Magnesium deficit was modeled by 10 week long magnesium deficient diet. After 54% lowering of magnesium level in erythrocytes we registered left ventricular pressure, myocardial contraction and relaxation rates, heart rate, systolic and diastolic arterial pressure, intensity of structures functioning. Than we subjected hearts of these animals to volume load, graded stimulation of cardiac adrenoreceptors, maximal isometric load by clamping ascending aorta. In animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit.

[Endothelial protection drugs--a new class of pharmacological agents].

This review considers issues dealing with the role of nitric oxide and endothelial function/dysfunction in providing a number of physiological and pathophysiological processes and various body systems functioning. It also covers in details the possible ways of pharmacological management of endothelial dysfunction (ED) using drugs of different pharmacological groups (classes). Diverse pharmacological effects which have various degree of intensity and presented at various stages of ED pathogenesis are discussed. The value and urgency of search and development of agents with endothelial protection potential are studied in available experimental and clinical works on the considerable role of endothelial system in cardiovascular diseases and lack of specific means for prevention and treatment of endothelial dysfunction. Integrated morphological-functional approach to assessment of ED and endothelial protection of substances was developed and implemented in experimental practice in Cardiovascular Agents Laboratory of the Volgograd State Medical University Research Institute of Pharmacology. Various ED models were tested and most valid ones were selected. Endothelial protection of new compounds such as Salifen and Flavicin are considered and compared with cardiovascular drugs, antioxidants with metabolic effects, GABA derivatives. These drugs are assumed to belong to a new class of drugs--endothelial protection drugs.

[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.

[Effects of mexidol and sulodexide on the level of specific markers of endothelial dysfunction in animals with experimental diabetes mellitus].

Streptozotocin-induced diabetes leads to the development of endothelial dysfunction, as evidenced by decreased expression of endothelial nitric oxide synthase (eNOS) and increased expression of endothelin-1 as specific markers of endothelial disorders. All test substances showed endotelioprotective activity by increasing the concentration of eNOS and reducing the level of endothelin-1. With respect to the degree of impact on the eNOS and endothelin-1 levels, the compounds studied can be rated as follows: sulodexide > meksidol.

[Effect of phenibut and its composition with nicotinic acid on hemostasis in rats with brain ischemia].

It is shown that, in rats with global cerebral ischemia modeled by a complete irreversible occlusion of the common carotid artery and forced hypotension, the hemostasis is characterized by a shift toward hypercoagulation. A single preventive introduction of phenibut and, to a greater degree, a composition of phenibut with nicotinic acid, in rats with acute cerebral ischemia reduced the extent of disturbances in the hemostasis system of experimental animals.

[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.