Conditioned Passive Avoidance Reflex Research Articles

Neuroprotective effect of Orostachys spinose dry extract in cholinergic insufficiency

Background. Orostachys spinosa (L.) Sweet. – a perennial plant of a wide habitat and contains various metabolites (amino acids, flavonoids, polysaccharides, etc.). Extracts from the aerial part of the plant are used in traditional medicine as an anticonvulsant and sedative.The aim of the work. To study the neuroprotective effect of O. spinosa in cholinergic deficiency.Materials and methods. The studies were carried out on 52 Wistar rats. The animals were administered scopolamine (1 mg/kg) daily for 21 days, followed by O. spinosa dry extract per os at a dose of 100 mg/kg for 14 days. On the day 32, the animals developed a conditioned passive avoidance reflex (CPAR), the integrity of which was checked after 1, 24 and 72 hours; on the day 35 they were tested in an “open field”. On the day 36, biochemical and histological studies of the brain were carried out.Results. It has been established that O. spinosa, against the background of scopolamine intoxication, reduces the anxiety of animals, stimulates exploratory activity in the open field test, improves the production and preservation of the CPAR, and also reduces the number of functionally inactive neurons (pyknotic and shadow cells) in the cerebral cortex. The extract reduces the lactate/pyruvate ratio by 47 %, intensifies the activity of mitochondrial complexes I and II by 54–64 %, and increases the concentration of adenosine triphosphate by 1.6 times compared to the control. O. spinosa exhibits antioxidant properties by reducing malondialdehyde and increasing the activity of catalase, glutathione peroxidase and glutathione reductase in the brain.Conclusion. O. spinosa dry extract has a neuroprotective effect in cholinergic deficiency. The studied extract exhibits antioxidant properties and stimulates energy processes in the brain

Physiological and biochemical in vivo study of polyphenols and 20-hydroxyecdisone from quinoa grains effect on resistance to physical exercise in Wistar rats

Increasing the ability of the human body to adapt to physical stress is relevant from the standpoint of using foods for special uses containing functional food ingredients (FFI) with effectiveness proven in vivo. The purpose of this study was to evaluate the effect of FFI from Chenopodium quinoa grains with a high content of polyphenols and phytoecdysteroids on the physical endurance of male Wistar rats. Material and methods. The experiment was carried out during 36 days using 50 weaned male Wistar rats. The animals were randomly divided into 3 groups (n=12): Control, Run and Run-FFI. Rats of the Control and Run groups received a standard semisynthetic diet during the experiment. Rats of the Run-FFI group received a semi-synthetic diet with the addition of FFI in an amount of 0.055±0.003%, containing phytoecdysteroids (50.4±0.6 mg/g) and polyphenols (212.0±2.0 mg/g). During the experiment, the rats were assessed for their neuromotor function (grip strength of front paws), memory, and behavioral reactions in the "Elevated Plus Maze" (EPM), "Conditioned Passive Avoidance Reflex" (CPAR) and "Open Field" (OF) tests. Once a week, animals from the Run and Run-FFI groups were subjected to moderate physical load on a "Treadmill". On the 36th day of the experiment, the animals of these groups were subjected to exhausting physical load. Immediately after running, the animals were placed in metabolic cages to collect daily urine. At the end of the experiment, the content of corticosterone, the activity of catalase, indicators of protein, lipid and mineral metabolism, indexes of the liver functional state and antioxidant defense system parameters were analyzed in the blood serum; the level of prostaglandin E2 and dopamine were determined in daily urine. Results. Physiological tests (CRAR, OF) showed that weekly exercise increased anxiety in laboratory animals. The FFI introduction into the diet led to normalization of the assessed parameters (EPM). As a result of 36-day consumption of FFI against the background of physical loads, a significant decrease by 22% in the main stress marker, corticosterone, was revealed in the blood of rats, as well as significant increase by 23% in the stress inhibitor - prostaglandin E2 urinary excretion, compared with animals of the Run group to the level not differed from the indicators of the control animals. There were no differences in endurance performance between the Run and Run-FFI groups on the results of the exhaustive exercise. Consumption of FFI prevented the formation of excess ammonia, significantly reducing the level of urea in the blood and normalizing its excretion to control levels in the urine, which was increased in the Run group by 19%. Conclusion. The results obtained demonstrated the adaptogenic properties of the developed FFI in response to stress caused by weekly moderate and acute exhaustive physical activity. The obtained data on the biological effect of the developed FPI on the adaptive potential of laboratory animals will serve as an experimental basis for its inclusion in the composition of specialized foods.

Study of the nootropic effect of the extract of <i>Scutellaria baicalensis Georgi</i> in modeling anxiety and depressive disorders in rats during the development of a conditioned reflex of passive avoidance

Experimental study is devoted to the study of the nootropic effect of the extract Scutellaria baicalensis Georgi in normal conditions and in modelling anxiety-depressive disorders by creating "social" stress in rats during the development of a conditioned passive avoidance reflex. Materials and methods. The study was made of the extract obtained by maceration of the underground part (rhizomes with roots) of the plant Scutellaria baicalensis Georgi. The experimental work involved the study of the behavioural characteristics of laboratory animals (non-linear rats) in the amount of 159 males aged 7-9 months, divided into groups in accordance with the stages of the study. The study of nootropic activity in the norm formed the basis of the first stage and included work with animals divided into 4 groups: receiving water for injection (intact); Scutellaria baicalensis Georgi extract, medicinal product «Tetramethyltetraazocycloocyandione»; medicinal product «Piracetam+Cinnarizine». The creation of conditions providing for paired sensory contact of individuals, contributing to the development of inter-male confrontations, was achieved by modelling “social” stress in groups identical to the normal state at the second stage of experimental work. The use of the standard setting of the passive avoidance conditioned reflex made it possible to analyse the cognitive functions of the animals. Results. The nootropic effect of Scutellaria baicalensis Georgi extract has been proven. The decrease in the consequences of stress in the form of a deterioration in memorization and reproduction of a conditioned reflex of passive avoidance was shown when it was administered to laboratory animals. Extension of the latent period of entry into the dark chamber of the passive avoidance conditioned reflex test, an increase in the total time spent in the illuminated compartment, and a decrease in the percentage of animals that visited the dark "aversive" compartment under the influence of the extract were described. Conclusion. The preservation of a memory trace in laboratory animals after the introduction of an extract made on the basis of Scutellaria baicalensis Georgi has been established. The presence of a complex of various groups of biologically active substances in the composition of the Scutellaria baicalensis Georgi determines this plant object as a source of obtaining new drugs recommended for use as nootropic drugs that reduce the reactions that develop during “social” stress.

Effect of Glutamate Antibody F(ab)2 Fragments on Memory Changes in Aged C57BL/6 Mice.

Intranasal administration of F(ab)2 fragments of anti-glutamate antibodies to 12-month-old C57BL/6 mice improves passive avoidance conditioning and have no effect on horizontal and vertical locomotor activity in the open-field test. In contrast to full-length antibodies to glutamate, their F(ab)2 fragments significantly increase the number of animals developed a conditioned passive avoidance reflex.

Effect of reindeer pituitary peptide extract on cognitive functions in rats with changes light regime

BACKGROUND: Disruption of circadian rhythms can cause significant damage to sensory processing, learning, and memory. At the same time, the structure of the endogenous biological clock contributes to the adaptation of the organism to changes in the conditions for the existence of a biosystem in the external environment. The possibility of synchronization of the endogenous rhythms of the organism with disturbed light periodicity is an urgent problem of modern society, where different rhythms of labor, motor, cognitive activity are used.
 AIM: To study the effect of peptides from the pituitary gland of the Reindeer on the parameters of cognitive functions in rats with a long-term change in the light regime on models with altered cellular oscillation due to oxidative stress caused by poisoning of animals with sodium thiopental in a half-lethal dose.
 MATERIALS AND METHODS: The study was conducted on 56 white Wistar male rats after acute poisoning with sodium thiopental at a dose of 85 mg/kg under conditions of light desynchronosis. In the passive avoidance conditioned reflex test, the cognitive functions of animals were assessed after a two-week pharmacological correction with a cellular extract of the pituitary gland of the Reindeer at a dose of 100 mg/kg.
 RESULTS: The peptide extract of the pituitary gland of the Reindeer contributes to the change in the higher integrative functions of the central nervous system in case of disturbed periodicity of the light signal. The results obtained indicate the chronobiotic activity of the peptide extract of the pituitary gland of the Reindeer at a dose of 100 g/kg when administered intranasally.
 CONCLUSIONS: The light regime change for 1 month under conditions of altered cellular oscillation led to impaired of the higher integrative functions of the central nervous system in rats, which was accompanied by an increase in the rate of reflex extinction and a disturbance of the processes of memory consolidation; under conditions of constant light, these disorders are more pronounced. The result of the pharmacological correction of these changes with the reindeer pituitary peptide extract was an improvement in the processes of memory consolidation and information reproduction (an increase in the number of trained animals with a change in the light regime).

Some pharmacological propertyes of Chamerion angustifolium infusions

BACKGROUND: Chamerion angustifolium has been popular among the people for many centuries as a substitute for tea and a mild sedative. Leaf infusions are used for neurosis, cephalgia, epilepsy and other neurological diseases.
 AIM: Was to experimentally confirm the cerebroprotective properties of Chamerion leaf infusions.
 METHODS: We used the methods of maximum electric shock, conditioned passive avoidance, and immobilization stress in rats and mice.
 RESULTS: Infusions of leaves experimentally revealed no anticonvulsant properties. Cerebroprotective properties were manifested in the preservation of the passive avoidance conditioned reflex after maximum shock and faster recovery of exploratory behavior. Distinct stress-limiting properties were revealed during immobilization stress in mice. Fermented leaves have been shown to be less effective than non-fermented ones.
 CONCLUSION: The data obtained confirm the presence of cerebroprotective properties of the infusion of Chamerion angustifolium.

DEVELOPMENT OF A TECHNIQUE FOR MODELING A DEPRESSIVE STATE IN RAT BY STEREOTAXIС INJECTION OF LIPOPOLYSACCHARIDE INTO THE HIPPOCAMPUS

Introduction: Currently, various mechanisms of the development of depression are known. At the beginning of the 21st century, a new era began in the study of the pathogenesis of this disease. It has been shown that the development of a depressive state is closely associated with neuroinflammation. As a result, it became necessary to develop methods for modeling depression, which will cause inflammation in a strictly defined area of the brain. Purpose of the work: Creation of a model of the depressive state in rats by stereotaxic injection of LPS into the hippocampus. Materials and Methods: Ten female Wistar rats were randomly divided into a control group (n = 3), an LPS-treated group (n = 4), and a sham-operated group (n = 3). LPS was administered at a dose of 30 μg / animal in a volume of 3 μL over 30 min, according to the following stereotaxic coordinates: AP: -3, ML: 2, DV: 3. Depression was assessed in psychopharmacological tests: hole-board test, open field, elevated plus maze, dark-light chamber, Porsolt forced swimming test, sucrose test. The formation of conditioned reflexes of passive avoidance was studied. To assess the localization of the injection, an MRI scan was performed on the 7th day. The result of LPS injection was analyzed on histological preparations. Results: During testing of animals in the setting of a dark-light chamber and an elevated plus maze, it was found that the control and sham-operated groups did not have statistically significant differences. At the same time, the time spent by the rats in the light compartments increased in the experimental group. In the Porsolt forced swimming test, there are statistically significant differences in the time of immobilization of animals. Also, in the rats of the experimental group, the latent period of the onset of reversible actions increased. The study of the formation of a conditioned passive avoidance reflex can be considered not indicative, since two rats from the experimental group and one rat from the group of sham-operated animals did not enter the dark compartment of the installation and did not receive training. In the test for anhedonia, the rats of the experimental group showed a decrease in the consumption of sucrose as compared with the animals of the comparison groups. On histological preparations of the brain at the injection site, the formation of a glial-macrophage "shaft" (hematoxylin-eosin staining) is observed. When analyzing the MRI images, it was proved that the injection was made precisely in the hippocampus of rats. Conclusion: Based on the results of the work, it can be concluded that this method of modeling depression is applicable in fundamental research, since the introduction of lipopolysaccharide into the hippocampus causes neuroinflammation in rats, and as a result, a depression state, and can be used to study the antidepressant activity of new drugs. This work was carried out with the financial support of the Russian Science Foundation grant No. 21-73-20250.

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia.

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

Antiamnestic effect of new nicotinic acid derivatives

Introduction: The search for new drugs for the prevention and treatment of vascular cognitive disorders continues to be a relevant task of pharmacology. In this regard, the aim of this work is to study the antiamnestic effect of five new nicotinic acid derivatives in comparison with the well-known drug mexidol (ethylmethylhydroxypyridine succinate) in animals.
 Materials and methods: The experiments were carried out on white male mice using conditioned passive avoidance reflex (CPAR). Electroconvulsive shock (ECS), scopolamine administration, and acute hypoxia in a hermetic chamber were used as amnesic effects. Testing for the safety of CPAR was performed 24 h after amnesic exposure. The new substances, reference drug mexidol, and a 0.9% sodium chloride solution (control group) were administered once intraperitoneally 60 min before mice training.
 Results and discussion: Three of the five new nicotinic acid derivatives, LKhT 4-19 (100 mg/kg), LKhT 6-19 (25, 50, and 100 mg/kg), and LKhT 7-19 (100 mg/kg), have antiamnestic properties on models of amnesia in mice induced by ESC, scopolamine, and acute hypoxia in a hermetic chamber. At the same time, the most efficient substance – LKhT 6-19 – exceeds the reference drug mexidol on all three models used. In addition, this compound is also more efficient than two other new compounds, LKhT 4-19 and LKhT 7-19, on the model of ESC-induced amnesia and LKhT 7-19 on the scopolamine-induced amnesia model.
 Conclusion: Compound LKhT 6-19 is promising for further advanced preclinical studies as a potential drug with antiamnestic activity.

Cognitive Dysfunction in the Offspring of Rats with Experimental Preeclampsia at the Early and Late Stages of Ontogeny and Its Correction with GABA Derivatives

We report here studies of cognitive impairments at different periods of ontogeny in the offspring of rats with experimental preeclampsia modeled by replacement of drinking water with 1.8% sodium chloride solution from day 1 to day 21 of gestation. The offspring of females with complications of pregnancy, at both the early (40 days and three months) and late (six and 12 months) stages of individual development showed decreases in working memory in the novel object recognition test, degraded formation and retention of memory traces in the conditioned passive avoidance reflex test, and more marked amnesia in response to scopolamine at a dose of 1.75 mg/kg on testing for retention of memory traces. Oral treatment of the offspring of females with experimental preeclampsia at pubertal age (from day 40 to day 70 of life) with GABA derivatives succicard, salifen, and phenibut, and reference agent pantogam, promoted decreases in cognitive deficit in animals at different periods of postnatal development.

Influence of the L-carnitine and resveratrol complex on physiological, biochemical and morphological indicators of normal and obese rats

Specialized products and dietary supplements, enriched with complexes of minor biologically active substances (BAS), are often offered as components of therapeutic diets in the treatment of obesity and metabolic syndrome. At the same time, the possible effects of the interactions of BAS when consuming a multicomponent product have not been studied enough. The aim - to study the action on rats' organism of a complex supplement (RС), containing resveratrol (Res) and L-carnitine (L-Car), when consumed with a standard balanced or hypercaloric diet. Material and methods. Male Wistar rats received for 63 days a standard balanced diet (SD) or a high-fat-high-carbohydrate diet (HFCD) with an excess of total fat (30%) and fructose (20% solution instead of drinking water), or the same diets supplemented with RС in a low (25 mg/kg body weight as Res and 300 mg/kg body weight as L-Car) or high (50 and 600 mg/kg body weight, respectively) doses. The muscle grip strength, behavioral reactions in tests of the conditioned passive avoidance reflex (CPAR) and elevated plus maze (EPM) were studied. At the end of the experiment, the mass of adipose tissue and internal organs was determined together with the activity of microsomal and cytosolic liver enzymes for specific substrates, plasma biochemical parameters, liver morphology by lightoptical microscopy, accumulation of lipofuscin-like granules (LLG) in the liver and kidneys by laser confocal microscopy. Results. In the rats fed HFCD, compared with SD, there was an increase in the mass index of liver, total inguinal and retroperitoneal white adipose tissue, in the levels of glucose and triglycerides, in the activity of hepatic CYP1A1 and CYP3A monooxygenases, UDPglucuronosyltransferase, heme oxygenase, and simultaneous decrease of high and low density lipoprotein cholesterol, and quinone oxidoreductase activity. The RС intake stimulated the locomotor activity of rats in EPM, however, this effect was less pronounced against the background of HFCD consumption. In rats consuming SD (but not HFCD), the addition of RС caused an increase in search activity and anxiety according to the EPM and CPAR data. The effect on short- and long-term memory retention was statistically insignificant. RС intake did not have hypolipidemic and hypoglycemic properties but caused in low dose an increase in the ratio of the activity of transaminases AST/ALT in animals fed HFCD. The liver CYP3A activity increased in rats supplemented with RС in high dose fed HFCD. In the kidneys of animals, the consumption of RС resulted in increased accumulation of LLG. Conclusion. When studying the effect of the complex supplement RС on normal and obese rats according to the studied physiological, morphological and biochemical indexes, no positive effects were revealed, that would not have manifested themselves for Res and L-Car separate intake. No evidence of synergistic action of L-Car and Res were found, and some of the effects of the complex supplement can be considered as adverse. This requires careful assessment when combined using these substances in complex diet therapy of metabolic disorders in humans.

Prolonged Social Isolation, Started Early in Life, Impairs Cognitive Abilities in Rats Depending on Sex.

Background: The chronic stress of social isolation is a valid predictor of cognitive pathology. This study aimed to compare the effects of long-term social isolation on female versus male Wistar rats’ learning and memory. We hypothesized that prolonged social isolation stress, which starts early in life, would affect learning in a sex-dependent manner. Methods: Social isolation started at the edge of early to mid-adolescence and lasted 9 months. The rat’s cognitive abilities were assessed by habituation and reactivity to novelty in the open field (OF) test, spatial memory in the Morris water maze (MWM), and the conditioned passive avoidance (PA) reflex. Basal serum corticosterone levels were assessed using an enzyme-linked immunosorbent assay. Results: Regardless of the housing conditions, females habituated to the OF under low illumination slower than males. Under bright light, the single-housed rats showed hyporeactivity to novelty. In the MWM, all the rats learned to locate the platform; however, on the first training day, the single-housed females’ speed was lower relative to other groups. Four months later, in the post-reminder probe trial, the single-housed rats reached the area around the platform site later, and only males, regardless of housing conditions, preferred the target quadrant. Single-housed rats, irrespective of sex, showed a PA deficit. There was a more pronounced conditioned fear in the single-housed males than in females. In both male and female rats, basal corticosterone levels in rat blood serum after 9 months of social isolation did not differ from that in the group-housed rats of the corresponding sex. Meanwhile, females’ basal corticosterone level was higher than in males, regardless of the housing conditions. The relative weight of the adrenal glands was increased only in single-housed females. Conclusions: Under long-term social isolation, started early in life, single-housed females compared with males showed more pronounced cognitive impairments in the MWM and PA paradigm, findings that specify their greater vulnerability to the stress of prolonged social isolation.

Geroprotective effects of ethylmethylhydroxypyridine succinate in an experimental study

To study an effect of mexidol on the life expectancy, weight, seizure response thresholds, and impaired cognitive and motor functions during aging in male Wistar rats. In a long-term experiment, male Wistar rats, aged 3-26 months, were assessed for impaired cognitive functions (passive avoidance conditioned reflex test), convulsive threshold (test with pentylenetetrazole), motor deficits (tests of rotating rod and pulling on the crossbar), and life expectancy. The rats received mexidol in the form of 0,15% solution, which replaced drinking water, during two 2 month courses at the age of 18-20 and 22-24 month. A dose of mexidol consumed by the rat was 40-75 mg/kg/day. In old male Wistar rats, the long-term treatment with mexidol increases the life expectancy, improves learning, preservation and reproduction of the memory trace in the passive avoidance conditioned reflex test, increases the convulsive threshold and improves muscle tone and coordination of movements that are impaired during aging. Mexidol increases the threshold of convulsive reaction, restores cognitive and neurological deficits that occur during aging in male Wistar rats and increases the by its ability to influence mitochondriogenesis and antioxidant properties.

Variation of spacer type and topology of phenyl moiety in 2-pyridone core of 4-oxo-3-N-methylcytisine; effect of synthesized compounds on rat’s behavior in conditioned passive avoidance reflex (CPAR) test

Novel derivatives of 4-oxo-3-methylcytisine with phenyl moiety bonded to starting molecule through various spacers were obtained from the 9-amino, -halo, -formyl and 11-halo precursors by reductive alkylation of amines, generation of amide, as well as thio- and carboxamide functions, cross-coupling reactions, aldehyde condensation and reduction of unsaturated ‘C-C’ bonds. Ability of synthesized compounds to influence the learning and memory was preliminary assessed in conditioned passive avoidance reflex (CPAR) test in rats. It was shown, that derivatives with phenyl group at 11 carbon atom influence the learning and memory in CPAR test more effectively than other compounds. The hit-compound (3-methyl-11-(2-phenylvinyl)-3,5,6-trihydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-4,8(1H)-dione) with the best values of ‘latency’ and ‘time spent in the dark compartment’ has been identified as a perspective scaffold for synthesis of novel derivatives of (-)-cytisine with potential neuropharmacological activity.

Assessment of the Effects of Cell Therapy on Reproduction of the Conditioned Passive Avoidance Reflex in Rats with Quinoline-Induced Model of Huntington’s Disease

Introduction: The model involving injection of quinolinic acid (QA) into the rat striatum simulates many clinical and morphological characteristics of Huntington’s disease (HD). Searching for effective treatment methods is rather important because of the fatality of HD. One of such methods is to create a neuroprotective environment to slow down the current degenerative process and/or replace dead neurons. In particular, this can be performed by transplantation of cells capable of neuronal differentiation and integration into the proper structural and functional brain networks. Objective: To assess effectiveness and safety of transplantation of neural precursor cells differentiated from induced pluripotent stem cells (iPSCs) taken from a healthy donor into the striatum of rats with QA-induced model of HD. Materials and methods: The effects of neurotransplantation on reproduction of the conditioned passive avoidance reflex were studied in rats with the HD model induced by injection of QA into the caudate nuclei of the striatum. In the study group (n = 8), human neural progenitors (1 × 106 per 10 µL of normal saline unilaterally, on the injured side) derived from iPSCs taken from a healthy donor were injected into the caudate nuclei as the transplanted material; normal saline was injected to the control group. The conditioned passive avoidance responses were tested with the ShutАvoid 1.8.03 software on a Harvard apparatus (Panlab, Spain). Results: When testing the reproduction of the passive avoidance responses, we found that injection of QA into the caudate nuclei of the rat brain reliably reduced the conditioned responses. Neurotransplantation of neural progenitors derived from iPSCs had a clear therapeutic effect and reinforced the passive avoidance reflex. During the entire testing period (7 days after exposure to the pain stimulus), the experimental animals either did not visit the dark compartment at all or visited it with a long latency period. Conclusions: Experimental neurotransplantation using iPSC derivatives allowed to improve storage of trace memory in rats with QA-induced model of HD, which contributes to correction of cognitive impairments caused by administration of the neurotoxin.

Нейропротективный и антиамнестический эффекты комбинированной терапии при ишемическом повреждении префронтальной коры в эксперименте

Цель исследования - изучение влияния комбинированной терапии (мутантные молекулы эритропоэтина (EPO) и дипептидный миметик фактора роста нервов ГК-2H) на воспроизведение условного рефлекса пассивного избегания (УРПИ) и объем поражения коры мозга у крыс с двусторонним ишемическим повреждением префронтальной коры. Методика. Мутантные молекулы EPO (MЕРО-TR и MЕPО-Fc) с значительно редуцированной эритропоэтической и выраженной цитопротекторной активностью созданы методом генной инженерии. Используемый миметик фактора роста нервов человека, эндогенного регуляторного белка, в экспериментах in vitro проявлял отчетливые нейропротективные свойства. Двустороннюю фокальную ишемию префронтальной коры головного мозга крыс создавали методом фотохимического тромбоза. Выработку и оценку УРПИ проводили по стандартной методике. Объем повреждения мозга оценивался при помощи МРТ. MEPO-TR и MEPO-Fc (50 мкг/кг) вводили интраназально однократно через 1 ч после фототромбоза, ГК-2Н (1 мг/кг) - внутрибрюшинно через 4 ч после фототромбоза и далее в течение 4 послеоперационных суток. Результаты. Выявлено статистически значимое сохранение выработанного до ишемии УРПИ, а также значимое снижение объема повреждения коры при комплексной терапии. Полученные данные свидетельствуют об антиамнестическом и нейропротекторном эффектах примененной комбинированной терапии, которые наиболее отчетливо выражены в дозах: МEPO-Fc (50 мкг/кг) и ГК-2Н (1 мг/кг). Заключение. Подтвержден нейропротекторный эффект и усиление антиамнестического эффекта при сочетанном применении мутантных производных эритропоэтина - MEPO-TR и MEPO-Fc и дипептидного миметика фактора роста нервов человека ГК-2H. The aim of this study was to investigate the effect of combination therapy, including mutant erythropoietin molecules (EPO) and a dipeptide mimetic of the nerve growth factor, GK-2H, on the conditioned passive avoidance (PA) reflex and the volume of injury induced by bilateral ischemia of the prefrontal cortex in rats. Using the method of genetic engineering the mutant molecules of EPO, MERO-TR and MEPO-Fc, with strongly reduced erythropoietic and pronounced cytoprotective activity were created. The used human nerve growth factor mimetic, an endogenous regulatory protein based on the b-bend of loop 4, which is a dimeric substituted dipeptide of bis- (N-monosuccinyl-glycyl-lysine) hexamethylenediamine, GK-2 human (GK-2H), has proven neuroprotective in in vitro experiments. Methods. Bilateral focal ischemic infarction was modeled in the rat prefrontal cortex by photochemically induced thrombosis. The PA test was performed according to a standard method. Volume of brain injury was estimated using MRI. MEPO-TR, and MEPO-Fc (50 mg/kg, intranasally) were administered once, one hour after the injury. GK-2Н (1 mg/kg, i.p.) was injected four hours after the injury and then for next four days. Results. The study showed that the complex therapy provided statistically significant retention of the PA reflex developed prior to ischemia and a significant decrease in the volume of injury. The anti-amnestic and neuroprotective effects of combination therapy were most pronounced at doses of MEPO-Fc 50 mg/kg and GK-2H 1 mg/kg. Conclusion. This study has confirmed the neuroprotective effect and enhancement of the anti-amnestic effect exerted by the combination of mutant erythropoietin derivatives, MEPO-TR and MEPO-Fc, and the dipeptide mimetic of human growth factor GK-2H.

Эффект дипептидного миметика фактора роста нервов человека ГК-2h на модели инсульта

Исследована нейропротекторная активность дипептидного миметика 4-й петли молекулы фактора роста нервов (NGF) человека, бис-(N-моносукцинил-глицил-L-лизина), ГК-2h на модели геморрагического инсульта (ГИ), вызванного интрацеребральной посттравматической гематомой (ИПГ). Установлено, что ГК-2h в дозах 0,1 и 1 мг/кг при субхроническом (5 дней) внутрибрюшинном введении оказывал защитный эффект у крыс с ИПГ при регистрации эффектов в течение 14 дней. ГК-2h уменьшал количество погибших от инсульта животных, оптимизировал ориентировочно-исследовательское поведение в открытом поле, предупреждал амнезию условного рефлекса пассивного избегания (УРПИ), вызванную ИПГ. Морфометрические исследования показали, что ГК-2h увеличивает у крыс с ИПГ плотность выживших нейронов в V-слое неокортекса. Наиболее отчетливо эффект ГК-2h проявлялся в дозе 1 мг/кг.

Neuromotor Activity, Anxiety and Cognitive Function in the In Vivo Model of Alimentary Hyperlipidemia and Obesity.

Behavioral indicators characterizing specific features of the pathological process of alimentary-dependent diseases were studied using in vivo model of alimentary hyperlipidemia in rats and mice. Rats and mice of the control groups received balanced semisynthetic diet for 63 days; animals of the experimental groups received a diet with high fat content (30% dry weight), balanced or high-fat diet with fructose solution instead of water, balanced cholesterol-enriched diet (0.5% dry weight), or balanced cholesterol-enriched diet with fructose solution. During the experiment, the mass of food, consumed by the animals, was monitored daily. Muscle tone was assessed by the front paw grip strength on days 33 and 54 of the experiment. Anxiety was tested in the elevated plus maze on days 36 and 57. Behavior and memory were assessed by conditioned passive avoidance reflex on days 39, 40, and 61. A significant increase in muscle tone was revealed on day 54 in rats fed with a balanced diet with fructose, and in mice, that received a similar diet, supplemented with fructose and cholesterol. Anxiety in the second test (day 57) was significantly decreased in rats fed high-fat diet and increased in mice fed high fat diet and high fat diet with fructose. In the second test, additional amount of cholesterol in the diet was the factor that significantly improved both short-term and long-term memory in both species. In mice, in contrast to rats, addition of fructose, including combination with high-fat diet, significantly worsened short-term and long-term memory. Thus, dietary factors, contributing to alimentary dyslipidemia development in rats and mice, can significantly affect the indices of neuromotor activity, anxiety level and cognitive functions, and the nature and direction of these changes are largely species-specific.

EFFECTS OF THE LITHIUM – CONTAINING SORBENT ON TERMS OF BEHAVIORAL REACTIONS UNDER CHRONIC ALCOHOL INTOXICATION MODEL

Lithium preparations are widely used for stabilize mood in case of bipolar affective disorder. Currently neuroprotective and neuroregenerative effects of lithium are of interest as in case of acute brain injury, also in chronic neurodegenerative diseases such as dementia, alcoholism, Alzheimer disease, etc. [1–5]. In clinical practice use of lithium preparations is limited due to difficult adjustment of drug dosage, necessity of monitoring its concentration in blood, side effects development as a result of accumulation of lithium in a body. For the purpose of improvement of pharmacologic properties lithium is combined with other agents (for example modifying sorbent) thus it can produce longer-term and more harmless (less side reactions) effect in the long view. Lithium immobilization on sorption basis will allow to use sorbent as detoxicant and carrying agent of drugs to body. The purpose of the work is studying the effect of the lithium – containing sorbent on terms of behavioral reactions under chronic alcohol intoxication model. Materials and methods. During the work we used nonlinear mice – males, which weight 25–30 g (180 animals). Chronic alcohol intoxication was precipitated via 40% proof spirit injections (oral supplementation in quantity of 3 g/kg during 2 weeks), additionally mice drunk 5% proof spirit from drinking bowl. Each experimental group consisted of 10 animals. Study drugs were inserted inside while ethanol injecting. Control animals were inserted 0,9% salin solution. Emotional state of animals was assessed through forced swim test, short – term memory assessment was performed through conditioned passive avoidance reflex. Effect of chronic alcohol intoxication on the parameters of conditioned reflex activity was measured every 7 days. Results. It was found that the investigated lithium-containing sorbent increases: the number of mice are trained passive avoidance reflex, remembering percent of electric shock animals compared to the negative control , and – the duration of the latent time of immobility in comparison with the negative control. Conclusion. The proposed formulation of lithium (immobilized on a sorbent ) has a complex neurotropic action, showing antitoxic properties against a background of long-term administration of ethanol.

New (−)−Cytisine Derivatives with Nootropic Activity

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (−)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N′-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.