Antioxidant system alterations and physiological characteristics of neonatal and juvenile DAT-KO rats.

Dopamine transporter knockout (DAT-KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine accumulation in the synaptic cleft and the prolonged action of dopamine on neurons. Animals with DAT deficiency are characterized by hyperactivity, stereotypy, cognitive deficits, and impairments in behavioral and biochemical indicators. Several key pathophysiological mechanisms are known to be common to psychiatric, neurodegenerative, metabolic, and other diseases. Among these mechanisms, oxidative stress systems play a particularly important role. One of the main antioxidant systems in the brain is glutathione: specifically, glutathione S-transferase, glutathione reductase, and catalase play a significant role in the regulation of vital oxidative processes, and their dysfunction has been shown in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases. The current study aimed to analyze the dynamics of the activity levels of glutathione reductase and glutathione S-transferase in erythrocytes, as well as catalase in the blood plasma, of DAT-deficient, homo- and heterozygous, neonatal and juvenile rats (both male and female). Their behavioral and physiological parameters were evaluated at the age of 1.5 months. For the first time, changes in physiological and biochemical parameters were shown in DAT-KO rats at 1.5 months of postnatal life. The key role of glutathione S-transferase, glutathione reductase, and catalase in the regulation of oxidative stress in DAT-KO rats at the 5th week of life was demonstrated. A positive effect of a slightly increased dopamine level on memory function was shown in DAT-heterozygous animals.

Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin.

Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs. Other researchers showed that EPO can act as a protectant against severe brain injury and status epilepticus in rats. Therefore, we tried rhLF as a protector against the severe neurologic disorders developed in rats, such as the rotenone-induced model of Parkinson's disease and experimental autoimmune encephalomyelitis as a model of multiple sclerosis, and observed its capacity to mitigate the grave symptoms. Moreover, an intraperitoneal injection of rhLF into mice 1 h after occlusion of the medial cerebral artery significantly diminished the necrosis area measured on the third day in the ischaemic brain. During this period EPO was synthesized in various murine tissues. It was known that EPO induces nuclear translocation of Nrf2, which, like HIF-1-alpha, is a transcription factor. In view that under conditions of hypoxia both factors demonstrate a synergistic protective effect, we suggested that LF activates the Keap1/Nrf2 signaling pathway, an important link in proliferation and differentiation of normal and malignant cells. J774 macrophages were cultured for 3 days without or in the presence of ferric and ferrous ions (RPMI-1640 and DMEM/F12, respectively). Then cells were incubated with rhLF or Deferiprone. Confocal microscopy revealed nuclear translocation of Nrf2 (the key event in Keap1/Nrf2 signaling) induced by apo-rhLF (iron-free, RPMI-1640). The reference compound Deferiprone (iron chelator) had the similar effect. Upon iron binding (in DMEM/F12) rhLF did not activate the Keap1/Nrf2 pathway. Added to J774, apo-rhLF enhanced transcription of Nrf2-dependent genes coding for glutathione S-transferase P and heme oxygenase-1. Western blotting revealed presence of Nrf2 in mice brain after 6 days of oral administration of apo-rhLF, but not Fe-rhLF or equivalent amount of PBS. Hence, apo-LF, but not holo-LF, induces the translocation of Nrf2 from cytoplasm to the nucleus, probably due to its capacity to induce EPO synthesis.

[Telomere-telomerase system in aging, norm and pathology (literature review)].

This literature review presents results of research showing association between functional activity of the telomere-telomerase system and mental cognitive and emotional processes in normal and various pathological states: chronic stress, depression, bipolar disorder, schizophrenia, mild cognitive impairment and dementia in aging. It also refers to age-specific, psycho-social, economic, immunological, genetic and epigenetic factors that influence these relationships.

Impairment of non-associative learning in a rat experimental model of preclinical stage of Parkinson's disease.

An experimental model of the preclinical stage of Parkinson's disease was induced by double intranasal administration of the proteasome inhibitor lactacystin. The results demonstrated signs of cognitive impairments expressed as impaired non-associative learning. This was related to degeneration of one-third of dopaminergic neurons in the ventral tegmental area of the midbrain and their axons in the dorsolateral prefrontal cortex. Impairment of non-associative learning may be an early non-motor marker of Parkinson's disease indicating the start of neurodegenerative processes in the dopaminergic mesocortical system of the brain.

Modification of Anxious Behavior after Psychogenic Trauma and Treatment with Galanin Receptor Antagonist.

Effects of blockage of central galanin receptors on anxiety manifestations were studied in rats with psychogenic trauma. Psychogenic trauma was modeled by exposure of a group of rats to the situation when the partner was killed by a predator. Antagonist of galanin receptors was intranasally administered before stress exposure. Animal behavior was evaluated using the elevated-plus maze test, free exploratory paradigm, and open-field test. Psychogenic trauma was followed by an increase in anxiety level and appearance of agitated behavior. Blockage of galanin receptors aggravated behavioral impairment, which manifested in the pathological anxious reactions - manifestations of hypervigilance and hyperawareness. The results suggest that endogenous pool of galanin is involved into prevention of excessive CNS response to stressful stimuli typical of posttraumatic stress disorder.

Behavioral, hormonal, and neurotransmitter reactions to stress in adult rats with a history of high IL-1ß content in the early postnatal ontogeny.

Behavioral, hormonal, and neurotransmitter reactions to foot shock were studied in adult rats treated with IL-1ß during week 3 of life. After stress, these animals differed from controls treated with saline by high levels of dopamine, serotonin, and 5-hydroxy-indolacetic acid in the hypothalamus. In contrast to controls, they developed a significant stress-induced increase of blood corticosterone level and exhibited lesser motor and exploratory activities in the open field test.

[Clinical parameters and the level of certain cytokines in blood and cerebrospinal fluid of patients with Parkinson's disease].

In the past decade, much attention has been given to immunological mechanisms of development of Parkinson's disease with special reference to the role of pro- and anti-inflammatory cytokines. The study was aimed at elucidating the cytokine status of PD patients taking account of the stage, duration, and clinical manifestations of the disease. It was shown that PD patients regardless of severity of the disease had elevated serum and liquor IL-1ß and IL-6 levels compared with controls while the I-IRA level was decreased. Patients with predominantly left-side localization of PD had an elevated blood TNFα level. It was shown for the first time that the cytokine profile in PD patients varies with progression of disease. The high rate of progression was associated with the high liquor TNFα level and blood IL-1ß level compared to the patients with moderate and slow progression. The blood IL-10 level was found to be related to the degree of anxiety and depression whereas the TNFα level correlated with the severity of cognitive deficit.

[Impairments of conditioned behavior in adult rats induced by interleukine-1beta treatment in early postnatal ontogenesis].

Impairments of cognitive functions in children and adolescents are often consequences ofperinatal pathology (natal injuries, ischemia, hypoxia, infection and allergic diseases), which are accompanied by enhanced production ofproinflammatory cytokine interleukine-1beta. In this work it was shown that treatment with interleukine-1beta during the third week of life impaired active and passive avoidance conditioning in adult rats at the age of 60-70 days.

[Polyunsaturated fatty acids prevent the development of locomotor disturbances caused by changes in the neurohumoral background in rat pups].

The present study shows the effectiveness of using polyunsaturated fatty acids in pregnant rats in order to prevent behavioral alterations in neonatal rats caused by the action of the pathogenic peptide factors of blood serum with perinatal damage of the central nervous system.

Long-term disorders of behavior in rats induced by administration of tumor necrosis factor during early postnatal ontogenesis.

The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) is one of the main mediators of neuroimmune interactions. Increased production of TNFalpha in nerve and immune system cells occurs in infectious diseases, traumas, ischemia, and hypoxia. The present study addressed the role of TNFalpha in the formation of behavior during early postnatal ontogenesis. TNFalpha was given to rats during the third week of life and behavior was tested at ages 1.5 and 3 months using the open field test and the elevated plus maze test. Experimental rats differed from controls in terms of changes in orientational behavior on testing at 1.5 months and an increase in anxiety on testing at 1.5 and 3 months. The different roles of proinflammatory cytokines in the brain at the early stages of ontogenesis are discussed.

The role of the neuropeptide galanin in forming type-specific behavioral characteristics.

Intranasal administration of a galanin receptor blocker to rats was found to change their behavioral type on being placed in an unfamiliar environment, with decreases in movement and investigative activity and increases in the level of anxiety in the open field test. The basal level of expression of the galanin precursor mRNA in the anterior hypothalamus was significantly higher in rats with the active type of behavior in the open field test. In conditions of galanin receptor blockade, there was also a faster increase in the serum corticosterone level in response to a stress situation (forced swimming test), which was accompanied by a reduction in the immobilization time. These data support the involvement of galanin in the formation of individual-typological behavioral characteristics and demonstrate its important role in adaptation to stress.

[The intestinal microbiota composition in patients with multiple sclerosis receiving different disease-modifying therapies DMT]. / Osobennosti sostava mikrobioty kishechnika u patsientov s rasseiannym sklerozom, poluchaiushchikh preparaty, izmeniaiushchie techenie rasseiannogo skleroza.

AIM: To describe characteristics of the intestinal microbiota in patients with multiple sclerosis (MS) treated with glatiramer acetate (GA) or fingolimode (FG) for understanding causal relationships between gut microbiota and autoimmune processes in MS patients. MATERIAL AND METHODS: The study included 34 patients treated with GA (n=17) or FG (n=17). GA was used in a dose of 20 mg/kg subcutaneously once a day, FG in a dose of 0.5 mg daily. All patients were examined during remission. To assess the composition of gut microbiota, bacteriological and real-time PCR techniques were used. DNA was extracted from feces using DNA-EXPRESS kit. RESULTS AND CONCLUSION: There was a decrease in numbers of Escherichia coli with normal enzymatic activity, which was replaced by atypical forms of E. coli, Enterobacter spp. and fungi of the genus Candida, and, during treatment with GA, by atypical forms of E. coli, Proteus spp., Parvimonas micra. These differences indicate the effect of the therapy on the intestinal microbiota composition.

The psychomodulatory action of subpyrogenic doses of interleukin-1beta in conditions of chronic administration to rats.

The effects of interleukin-1beta at low, subpyrogenic doses on behavior were studied in rats. Signs of increased anxiety were evident by day 5 of treatment courses. These results provide evidence supporting the role of proinflammatory cytokines in the pathogenesis of emotional disorders.

[Speach breasing optimization with biofeedback on respiratory arrythmia of heart rate].

Dynamics of physiological and psychological characteristics of healthy volunteers (adolescents and adults), speech professionals (logopedics), and stutter patients (adolescents and adults) in process of adoptive self-regulation with biofeedback on objective physiologic indicator - changes of respiratory arrhythmia of hart rate were investigated. High level of efficacy and practicability of the method application was revealed to study, diagnostics, optimization and correction of breathing, speech and behavior.

The effects of proinflammatory cytokines on the formation of behavior in early postnatal ontogenesis.

Studies were performed to investigate impairments to the formation of behavior arising as a result of increases in the proinflammatory cytokine interleukin-1beta in early postnatal ontogenesis. The cytokine was given at pyrogenic or subpyrogenic doses for one week (the first, second, or third week of life). Behavior was assessed at prepubertal age and in the adult state in the open field and elevated cross maze tests. The greatest changes were seen in adolescent rats given interleukin-1beta during the first or third weeks of life. Impairments were seen after administration of pyrogenic and subpyrogenic doses of cytokine and were identical in females and males. Changes consisted of partial substitution of acts, increases in motor activity and decreases in investigative activity. After sexual maturation, these behavioral impairments were no longer seen.

[MECHANISMS OF NEURONAL LOSS IN ALZHEIMER''S DISEASE].

One of the main elements of the pathogenesis of Alzheimer's disease is neuronal loss in different areas of the brain, which is more intensive than in normal aging. Necessity of studying the pathogenesis of this process is determined by the fact that the loss of neurons begins at the preclinical stage of Alzheimer's disease when the amyloid plaques and neurofibrillary tangles (main morphological manifestations of the disease) is not yet formed and that the loss of neurons correlates with the severity of clinical symptoms. To date, there is evidence that allows delineating probable pathogenetic mechanisms of neuronal loss. This is the purpose of this review of the literature.

[THE INTEGRATIVE LEVEL OF THE HIERARCHICAL SYSTEM OF SPATIAL ORIENTATION OF ANIMALS].

The purpose of this review is to analyze the current knowledge about the higher, integrative level of the physiological system of orientation of animals in space. The significance of the study of this level caused by the fact that its disruption can cause deterioration of the capacity for spatial orientation (spatial agnosia) which is an important sign of some diseases of the brain, and in particular Alzheimer's disease. In recent decades, the main functional components of integration of information on space position of animals were discovered. The significance of these discoveries was reflected in a number of prestigious awards and honors, including the Nobel Prize in Physiology or Medicine for 2014.

Enterococcus faecium strain L-3 and glatiramer acetate ameliorate experimental allergic encephalomyelitis in rats by affecting different populations of immune cells.

The effect of probiotic Enterococcus faecium strain L-3 was studied in rats with experimental allergic encephalomyelitis (EAE). Glatiramer acetate (GA) was used as control drug. E. faecium strain L-3 and GA both were able to reduce the severity of EAE in a similar fashion. Both approaches increased the proportion of EAE resistant rats and rats with mild disease, prolonged the inductive phase of EAE and reduced the disease duration. Study of the phenotypes of immune cells in blood revealed the differences in immunoregulatory pathways that mediate the protective action of probiotic or GA treatment of EAE. The presence of pronounced protective and immunomodulating effects of the probiotic E. faecium strain L-3 opens an opportunity of its application for the treatment of multiple sclerosis.

[EFFECT OF PROBIOTIC ENTEROCOCCI AND GLATIRAMER ACETATE ON THE SEVERITY OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN RATS ].

Currently intestinal microbiota is considered as a potential target for influence in various pathologies which have inflammation, autoimmunity or neurodegeneration in the genesis. Multiple sclerosis (MS) combines all these processes in the pathogenesis. Furthermore, the balance of the components of intestinal microbiota is disrupted during MS and followed by disbiosis. Different probiotics - bacteria with proven beneficial properties are widely used to correct dysbisis. In this paper, was investigated the ability of probiotic strain Enterococcus faecium L-3 to reduce disease severity in multiple sclerosis model - experimental allergic encephalomyelitis (EAE). E. faecium L-3 were used alone or in combination with glatiramer acetate (GA). It is shown that administration of E. faecium L-3 reduces the severity of EAE in rats almost as same as that of GA. However, when the probiotic enterococci administered together with GA the protective effect does not observed. It is assumed that these preparations stimulates different ways of the immune system, because their action stimulate different immune cells populations. The study demonstrates the ability of E. faecium L-3 to influence on the immune system in MS, directly and indirectly (through the correction of dysbiosis). This fact allows us to consider E. faecium L-3 as a potential tool for immunomodulation in autoimmune, inflammatory and neurodegenerative diseases.