Passive Avoidance Conditioning Research Articles

Ascending Vagal Sensory and Central Noradrenergic Pathways Modulate Retrieval of Passive Avoidance Memory in Male Rats.

Visceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay "gut feelings" to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. To examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. These new findings support the view that gut vagal afferents and the cNTSNA-to-vlBNST circuit play a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

The effect of surgical procedure in the nasal cavity in rats on the passive avoidance conditioning and the level of monoamines in the hypothalamus

In a biological model of septoplasty in rats, the effect of the operation on the passive avoidance conditioning (PAC) was studied. It has been shown that septoplasty increases anxiety and reduces exploratory activity in rodents under PAC. Neurochemical analysis of the hypothalamus carried out immediately after the end of the experiment revealed an increase in norepinephrine metabolism in rats after septoplasty, which may be associated with activation of the hypothalamic-pituitary-adrenal axis.

Antibodies to Glutamate Reduce the IL-6 Content in Cerebral Structures in Mice with Age-Related Memory Impairment.

Intranasal administration of antibodies to glutamate for 14 days improved passive avoidance conditioning and reduces the content of IL-6 within 7 days after their withdrawal in the prefrontal cortex and hippocampus of aging C57BL/6 mice.

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

INFLUENCE OF LOPHANTHUS CHINENSIS DRY EXTRACT ON THE MORPHOFUNCTIONAL STATE OF WISTAR RATS THE BRAIN DURING LONG-TERM ALCOHOLIZATION

The study purpose – to evaluate the effect of the Lophanthus chinensis dry extract on the Wistar rats brain morphofunctional state against the back-ground of long-term alcoholization. Material and methods. Alcohol intoxication was induced by long-term administration (6 weeks) of 40% ethanol in rats. Lophanthus chinensis dry ex-tract at a dose of 100 mg/kg was administered from the 3rd week of the experiment. On days 42-45, the animals were tested in an "open field", an el-evated plus maze, and they developed a conditioned passive avoidance reaction. After which a neurons pathomorphological study in the cerebral cor-tex was carried out. Results. It has been established that L. chinensis dry extract exhibits a neuroprotective effect during long-term alcohol intoxication, preventing the de-velopment of structural disorders in the cerebral cortex, thereby reducing anxiety and emotionality in animals, enhancing orientation-exploratory activity and normalizing mnestic functions. Conclusion. L. chinensis dry extract has a neuroprotective effect during long-term alcohol intoxication.

Evaluation of angiogenesis and microvascular remodeling in the subventricular zone of the brain of mice with experimental Alzheimer’s disease

BACKGROUND: Under the influence of external factors (learning), processes of microvasculature remodeling occur in the neurogenic niche to meet the metabolic needs of activated cells. However, it remains unclear how these mechanisms of brain plasticity are disrupted during neurodegeneration.
 AIM: To study the expression features of markers of angiogenesis and microvascular remodeling in the subventricular zone of the brain during training of animals, including against the background of the development of Alzheimer’s-type neurodegeneration in them.
 MATERIAL AND METHODS: The studies were carried out on C57BL/6 mice at the age of 8 months. Modeling of Alzheimer’s disease was carried out by intrahippocampal injection of 2 μl of a 1 mM solution of β-amyloid Aβ25-35. To assess cognitive deficits, a conditioned passive avoidance test using an aversive stimulus was used. The expression of LC3B, ZO1, VEGFR2, VEGFR3, CD146, ICAM2, Dll4, Tie2 in the subventricular zone per 100 DAPI-positive cells was assessed. The test results were processed using one-way ANOVA and Fisher's test, the Mann–Whitney U test, the results were considered significant at p 0.05.
 RESULTS: On the 9th day after the administration of β-amyloid, before the application of the aversive stimulus, an increase in the expression level of LC3 (7.95±5.83%, p=0.045), CD146 (18.35±0.01%, p=0.045) was recorded, as well as VEGFR3 (17.13±5.05%, p=0.045), which continued to increase after the presentation of the stimulus (26.61±0.01%, p=0.045). By the beginning of registration of cognitive impairment (38th day of the experiment), the expression level of VEGFR2 (20.61±2.8%, p=0.045) and ICAM2 (126.61±41.28%, p=0.045) increased, the content of Dll4 (29.66±8.72%, p=0.045) and Tie2 (36.39±7.8%, p=0.045) decreased in animals with experimental Alzheimer’s disease.
 CONCLUSION: An aversive stimulus stimulates microvascular remodeling mechanisms in the subventricular zone of the animal’s brain, but when exposed to β-amyloid, these processes are significantly disrupted.

The Effect of Surgical Procedure in the Nasal Cavity on the Passive Avoidance Conditioning and the Hypothalamic Level of Monoamines in Rats.

A rat biological model of septoplasty was used to study the effect of surgery on passive avoidance conditioning (PAC). Septoplasty was shown to increase anxiety and to reduce exploratory activity in rodents during PAC. A neurochemical analysis of the hypothalamus was carried out immediately after the end of the experiment and showed an increase in norepinephrine (NE) metabolism after septoplasty. The finding was tentatively associated with activation of the hypothalamic-pituitary-adrenal axis.

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.

Sex- and Strain-Related Differences in the Extinction of a Conditioned Passive Avoidance Reaction in DISC-L100P and C57BL/6 Mice

Sex- and Strain-Related Differences in the Extinction of a Conditioned Passive Avoidance Reaction in DISC-L100P and C57BL/6 Mice

Effects of Occupational Formaldehyde Exposure on Passive Avoidance Conditioning and Anxiety Levels in Wistar rats

Background: Formaldehyde is a volatile organic compound widely used in industry and medical fields such as Anatomy and Pathology. Exposure to this chemical negatively affects the skin, mucous membrane, and respiratory system. It can pass through the blood-brain barrier, potentially causing neurotoxicity. According to studies, formaldehyde might be involved in memory impairment and the cognitive decline process in Alzheimer disease (AD). Objectives: This study aimed to simulate chronic occupational formaldehyde exposure in rats and study its impacts on passive avoidance conditioning and anxiety. Methods: Twenty-four adult male Wistar rats were divided into four groups of 6 rats each. After an adaptation period, the rats were exposed to 1, 2, and 3 ppm formaldehyde vapor in an exposure chamber, 6 hours per day for 7 days. The control group was exposed to saline. After the exposure period, a shuttle box for passive avoidance conditioning and an elevated plus-maze test for assessing anxiety levels were performed. The data were analyzed by 1-way ANOVA and Duncan’s multiple range test for group comparison in SPSS and SAS software. Results: In the shuttle box test, formaldehyde dose-dependently decreased escape-through latency and increased the percentage of dark compartment entries (P<0.0001). In the elevated plus maze test, the percentage of time spent in open arms decreased by increasing the dosage (P<0.0001). Conclusion: Based on these findings, formaldehyde exposure can negatively alter brain function and cause memory impairment and anxiety.

Blockade of Ghrelin Receptor Signaling Enhances Conditioned Passive Avoidance and Context-Associated cFos Activation in Fasted Male Rats

Introduction: Interoceptive feedback to the brain regarding the body’s physiological state plays an important role in guiding motivated behaviors. For example, a state of negative energy balance tends to increase exploratory/food-seeking behaviors while reducing avoidance behaviors. We recently reported that overnight food deprivation reduces conditioned passive avoidance behavior in male (but not female) rats. Since fasting increases circulating levels of ghrelin, we hypothesized that ghrelin signaling contributes to the ability of fasting to reduce conditioned avoidance. Methods: Ad libitum-fed male rats were trained in a passive avoidance procedure using mild footshock. Later, following overnight food deprivation, the same rats were pretreated with ghrelin receptor antagonist (GRA) or saline vehicle 30 min before avoidance testing. Results: GRA restored passive avoidance in fasted rats as measured by both latency to enter and time spent in the shock-paired context. In addition, compared to vehicle-injected fasted rats, fasted rats that received GRA before reexposure to the shock-paired context displayed more cFos activation of prolactin-releasing peptide (PrRP)-positive noradrenergic (NA) neurons in the caudal nucleus of the solitary tract, accompanied by more cFos activation in downstream target sites of PrRP neurons (i.e., bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus). Discussion: These results support the view that ghrelin signaling contributes to the inhibitory effect of fasting on learned passive avoidance behavior, perhaps by suppressing recruitment of PrRP-positive NA neurons and their downstream hypothalamic and limbic forebrain targets.

Performance of the intracerebroventricularly injected streptozotocin Alzheimer’s disease model in a translationally relevant, aged and experienced rat population

The intracerebroventricularly (icv) injected streptozotocin (STZ) induced brain state is a widely used model of sporadic Alzheimer-disease (AD). However, data have been generated in young, naive albino rats. We postulate that the translationally most relevant animal population of an AD model should be that of aged rats with substantial learning history. The objective of the study was thus to probe the model in old rats with knowledge in various cognitive domains. Long-Evans rats of 23 and 10 months age with acquired knowledge in five-choice serial reaction time task (5-CSRTT), a cooperation task, Morris water-maze (MWM) and “pot-jumping” exercise were treated with 3 × 1.5 mg/kg icv. STZ and their performance were followed for 3 months in the above and additional behavioral assays. Both STZ-treated age groups showed significant impairment in the MWM (spatial learning) and novel object recognition test (recognition memory) but not in passive avoidance and fear conditioning paradigms (fear memory). In young STZ treated rats, significant differences were also found in the 5CSRTT (attention) and pot jumping test (procedural learning) while in old rats a significant increase in hippocampal phospho-tau/tau protein ratio was observed. No significant difference was found in the cooperation (social cognition) and pairwise discrimination (visual memory) assays and hippocampal β-amyloid levels. STZ treated old animals showed impulsivity-like behavior in several tests. Our results partly coincide with partly deviate from those published on young, albino, unexperienced rats. Beside the age, strain and experience level of the animals differences can also be attributed to the increased dose of STZ, and the applied food restriction regime. The observed cognitive and non-cognitive activity pattern of icv. STZ in aged experienced rats call for more extensive studies with the STZ model to further strengthen and specify its translational validity.

Psychopharmacological Effects of Stimulation of the Functions of Neural Stem Cells by STAT3 Inhibitor under Conditions of Modeled Ethanol-Induced Encephalopathy.

The psychopharmacological effects of a stimulator of functions of progenitor cells of the nervous tissue STAT3 inhibitor (STAT3 Inhibitor XIV, LLL12) were studied under conditions of modeled alcoholic encephalopathy in C57BL/6 mice. The pharmacological agent corrected the parameters of exploratory behavior (characterizing predominantly cognitive activity) in the experimental animals at the late terms of observation. At the same time, the reproducibility of the conditioned passive avoidance response developed at the beginning of the course STAT3 inhibitor administration decreased. These effects developed against the background of a significant increase in the content of neural stem cells and their proliferative activity in the paraventricular zone of the brain.

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies.

Aging-induced memory impairment is closely associated with oxidative stress. D-Galactose (D-gal) evokes severe oxidative stress and mimics normal aging in animals. Curcumin, a natural flavonoid, has potent antioxidant and anti-aging properties. There are several proteins like glutathione S-transferase A1 (GSTA1), glutathione S-transferase omega-1 (GSTO1), kelch-like ECH-associated protein 1 (KEAP1), beta-secretase 1 (BACE1), and amine oxidase [flavin-containing] A (MAOA) are commonly involved in oxidative stress and aging. This study aimed to investigate the interaction of curcumin to these proteins and their subsequent effect on aging-associated memory impairment in two robust animal models: D-Gal and normal aged (NA) mice. The aging mice model was developed by administering D-gal intraperitoneally (i.p). Mice (n = 64) were divided into the eight groups (8 mice in each group): Vehicle, Curcumin-Control, D-gal (100mg/kg; i.p), Curcumin + D-gal, Astaxanthin (Ast) + D-gal, Normal Aged (NA), Curcumin (30mg/kg Orally) + NA, Ast (20mg/kg Orally) + NA. Retention and freezing memories were assessed by passive avoidance (PA) and contextual fear conditioning (CFC). Molecular docking was performed to predict curcumin binding with potential molecular targets. Curcumin significantly increased retention time (p < 0.05) and freezing response (p < 0.05) in PA and CFC, respectively. Curcumin profoundly ameliorated the levels of glutathione, superoxide dismutase, catalase, advanced oxidation protein products, nitric oxide, and lipid peroxidation in mice hippocampi. In silico studies revealed favorable binding energies of curcumin with GSTA1, GSTO1, KEAP1, BACE1, and MAOA. Curcumin improves retention and freezing memory in D-gal and nature-induced aging mice. Curcumin ameliorates the levels of oxidative stress biomarkers in mice. Anti-aging effects of curcumin could be attributed to, at least partially, the upregulation of antioxidant enzymes through binding with GSTA1, GSTO1, KEAP1, and inhibition of oxidative damage through binding with BACE1 and MAOA.

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.&#x0D; AIM: Was to experimentally confirm the cerebroprotective properties of Chamerion leaf infusions.&#x0D; METHODS: We used the methods of maximum electric shock, conditioned passive avoidance, and immobilization stress in rats and mice.&#x0D; 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.&#x0D; 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.

INTEGRATIVE CENTRAL NERVOUS SYSTEM ACTIVITY OF RATS IN GERONTOGENESIS UNDER EXPERIMENTAL HYPERGLYCEMIA

Diabetes mellitus has a major impact on the brain and its cognitive function. The pathogenesis of these disorders is still not well understood. Therefore, it is necessary to find ways of solving these manifestations in hyperglycemia in order to prevent the risk of complications that will lead to a worsening of living conditions.&#x0D; In the experiment, the state of conditioned-reflex and orientation-research activity of rats of different ages (middle-aged rats and old rats) in conditions of experimental hyperglycemia was found. The animals were kept under standard vivarium conditions. Experimental hyperglycemia was modeled by intraperitoneal solution injection of alloxan monohydrate (120 mg/kg body weight, Sigma). For 10 days, blood glucose was determined using a portable glucometer «Bionime». On day 10, those animals were selected that had a blood glucose value above 28 mmol/L. The analysis of orientation-research and emotional activity was carried out using the «Open Field» technique. The number of squares crossed, the number of lifts on the hind legs, the number of peeking into the burrows, grooming, and the number of bowel movements were recorded. The conditioned passive avoidance technique was used to study the stable and labile phases of memory. In both age groups, the indicators of orientation-research activity differed significantly (p &lt; 0.05). The decrease in the number of squares crossed, the number of racks up and the study of minks was more pronounced in middle-aged animals with diabetes mellitus. The increase in the number of amnesiac animals was also more pronounced in the middle-aged rats of the research group. A decrease in the latency period was noted in both age groups. Thus, it was found that experimental hyperglycemia had pronounced consequences for the cognitive function of animals, respectively, diabetes mellitus has a negative effect on the brain.