


Том 110, № 3 (2024)
REVIEW
Meta-Analysis of Experimental Studies of the Effect of Melatonin Monotherapy on Body Weight Gain and Eating Behavior in Rats on Different Diets
Аннотация
In an earlier meta-analysis, we showed that long-term melatonin administration minimizes diet-induced changes in lipid profiles. The purpose of our present work was to use a meta-analysis to investigate the effect of melatonin monotherapy on body weight gain (BWG) and eating behavior in rats depending on diet. To this end, we conducted a meta-analysis of 43 publications examining the effects of melatonin monotherapy on BWG, leptin levels, food and water intake in rats fed a standard diet (37 publications), as well as high-fructose diets (5 publications) and fats (9 publications). Our findings suggest that although melatonin reduced the level of triglycerides, total cholesterol and leptin in rats fed high-fructose and high-fat diets but not those fed a standard diet, melatonin treatment prevented BWG in rats on either diet. Increasing the dose of melatonin did not enhance the effect of therapy with any of the diets studied. We did not obtain convincing evidence that the effect of melatonin depends on the initial body weight and age of rats. On a standard diet, melatonin has been found to reduce food and water intake. Melatonin did not reduce BWG with a standard diet when administered intraperitoneally. Our research suggests that melatonin may be beneficial for diet-induced metabolic disorders by improving lipid profiles and preventing BWG. However, a decrease in appetite and BWG when taking melatonin may also be associated with negative side effects of the drug, which requires further research.



Zebrafish аs а Promising Experimental Model of Traumatic Brain Injury
Аннотация
Traumatic brain injury (TBI) involves various types of physical injuries to brain tissue. TBI is a highly heterogeneous clinical condition, whose symptoms include cognitive, motor and emotional deficits, as well as neurodegeneration and neuroinflammation. Animal modeling plays a key role in studying TBI, expanding our knowledge of TBI and its temporal dynamics, and to develop new drugs for its treatment. Recently, the use of the bony zebrafish (Danio rerio) as an aquatic model organism has attracted particular interest in translational neurobiology. Zebrafish are presently second (after mice) laboratory animal species most used in biomedicine. Here, we discuss the prospects of using zebrafish to model TBI, as well as problems and new directions of research in this area. We also emphasize the importance of zebrafish as a highly translational model for studying the molecular mechanisms and neurological disorders in TBI, as well as screening for potential therapeutic agents.



The Role of Mast Cell-Neuron Tandem in the Regulation of Cardiac Function in Cardiovascular Pathologies
Аннотация
This review is consisted of new data about participation of mast cells (MCs) in the regulation of cardiac function in the development of some cardiovascular pathologies. In norm the number of MCs in the heart is very small compared to their number in barrier tissues. They are responsible for homeostasis of cardiac tissue and ensuring the interaction of the organ with the nervous and endocrine systems throughout the life of the organism.
Pathological processes in the heart are accompanied by the development of inflammation reaction. MCs fulfil a significant role in the all stages of inflammation. The number of MCs significantly increases against the background of myocardial infarction development, fibrotic heart disease and vascular atherosclerosis. Their contribution to the pathogenesis of the disease is ambiguous, because on the one hand it is aimed at tissue adaptation to damage, and on the other hand - avalanche-like synthesis and release of mediators from activated MCs aggravates the course of the process. As a result, MCs change their secretory profile, interfere in the realization of cardiac functions against the background of inflammation, but at the same time modulate afferent information flow from the heart and efferent influences of the nervous system. The coordinated work of the system loses its stability, which can lead to severe consequences for the vital activity of the whole organism.
The analysis of the current state of the problem indicates that the heart activity depends on the functional state of MCs, their complex interaction with the nervous system both in the norm and, especially, against the background of pathological processes development.



The Role of Titin Phosphorylation in Changes in Myocardial Stiffness in Cardiomyopathies
Аннотация
The review provides a brief analysis of current knowledge about such post-translational modification of titin as phosphorylation, with an emphasis on the changes that occur during the development of heart diseases. Studies conducted using animal models of heart disease, as well as using biomaterial from cardiac tissue from patients with various pathologies, show changes in the level of titin phosphorylation in comparison with healthy controls. As a rule, hyperphosphorylation of the S11878 site and hypophosphorylation of the S12022 site in the PEVK sequence of titin are observed, as well as changes in the level of phosphorylation of sites in the N2B sequence of this protein during the development of pathological changes. The functional effect of these changes is an increase in the stiffness of cardiomyocytes and cardiac muscle as a whole, which is based on the viscoelastic properties of titin, changes in which, in turn, are observed due to hypo- or hyperphosphorylation of certain sites of this protein. The review also provides a description of a number of therapeutic interventions aimed at changing the level of titin phosphorylation, which are considered as a way to change the viscoelastic properties of pathological myocardium in order to normalize its contractility.



EXPERIMENTAL ARTICLES
Definition of the Profile of Cognitive Deficit in Cardiac Surgery Patients Using the Optimal Clustering Method
Аннотация
An original clustering method based on discrete optimization of multidimensional objects according to many heterogeneous parameters: age, severity of carotid artery stenosis (CA), personal and cognitive characteristics was used to identify pre- and postoperative specificity of the profile of cognitive functions. The study involved 163 cardiac surgery patients. Determination of CA stenoses was carried out in the preoperative period using color duplex scanning and further classification of the lesion. Psychometric assessment of personal and situational anxiety, as well as psychomotor and executive functions, attention, short-term memory was performed 3–5 days before and 7–10 days after coronary artery bypass surgery (CABG). As a result of clustering arrays of 17 normalized indicators and subsequent analysis of three groups formed in this way, different dynamics of restoration of the profile of cognitive functions after coronary bypass surgery were discovered. One of the groups was designated as a group of cognitive reserves according to its best indicators of information selection and memory both in the preoperative and postoperative periods. Another selected group was characterized by a postoperative increase in the speed of information selection, but low memory scores. The third selected group demonstrated close relationships between indicators of attention, memory and the efficiency of a complex visual-motor reaction with age and the degree of stenosis of the CA, regardless of the pre- or postoperative testing period, which may indicate persistent disorganization of cognitive functions in such patients, requiring special attention when choosing neuro- and cardiac rehabilitation programs for them. The developed clustering method makes it possible to group patients according to a variety of heterogeneous parameters to identify the dynamics of their changes during the course of treatment.



Syndecan-1 as Potential Messenger of Effects of Remote Postconditioning in Experiments with Brain Ischemia
Аннотация
The mechanisms of cerebral reperfusion injury restriction by remote conditionig (RC) is interesting due to its possible effects on functional recovery after brain ischemia. The assessment of the role of syndecan-1 (SDC-1) and annexin-5 (ANXA5) content in blood plasma was performed by ischemic-reperfusion injury on middle cerebral artery model in rats. We used RC protocol. Randomized controlled trials were conducted. Ischemia had been done by MCAo (middle cerebral artery occlusion) by Belayev [6]. Animals used were the Wistar rat-males weighting 250 g. under general anesthesia (Zoletil 100 и Xylazine 2%). MCAo animals had been detected 41.4*±1.3 ng/ml SDC-1 plasma’s level (30%). MCAo animals with RC protocol had been detected 67.8**±5.8 ng/ml SDC-1 plasma’s level (112%). Infarction volume in MCAo animals’ brain reviled 31.97 ± 2.5% injury; the volume of infarction was 13.6 ± 1.3%. Swelling of tissue in МCАо animals with RC was 16 ± 2.1%; in contrary, in МCАо animals’ swelling of tissue was bigger up to 47 ± 3.3%. Correlation analysis in MCAo animals with RC reviled high direct correlation relationship between infarction area and muscle strength in the right forelimb (КК=0.72). Correlation analysis reviled very high inverse correlation between infarct area and capillary blood flow in МCАо animals with RC (p < 0.01; r = -0.98). It is being discussed the SDC-1 protein in blood plasma may play role of potential regulator of infarct–limiting effects of remote ischemic postconditioning which cause functional recovery.



Anakinra Promotes M2 Microglia Activation during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy
Аннотация
Astrocytes and microglia and their polarization are thought to contribute to the progression of epilepsy. One of the processes affecting polarization is neuroinflammation, which plays an important role in epileptogenesis. However, the specific mechanisms of its involvement in shifting the pro- and anti-inflammatory reactivation of astro- and microglia have not been clarified. In this study, we examined the effect of 7-day interleukin-1 receptor antagonist (anakinra) administration on glial cell polarization during the latent phase of the lithium-pilocarpine model in 7-week-old male Wistar rats. In temporal cortex, dorsal and ventral hippocampus the mRNA expression levels of the following genes were analyzed: (i) markers of astroglia (S100b) and microglia (Aif1) activation, (ii) astrocytic proteins involved in glutamate transport and metabolism (Slc1a3, Glul, Gja1), (iii) pro-inflammatory pathway interleukin-1β (Nlrp3, Il1b, Il1rn) and transforming growth factor β1 (Tgfb1), (iv) markers of astroglia polarization (Lcn2, S100a10, Gbp2, Ptx3), and (v) microglia polarization (Nos2 and Arg1). The mRNA expression levels of S100b and Aif1 were significantly increased, and anakinra administration did not reduce their overexpression. This indicates reactivation of astroglia and microglia regardless of the anakinra administered. The expression of Slc1a3, Glul, and Gja1 genes increased in the hippocampus; anakinra administration did not affect their hyperexpression, but promoted increased expression of Gja1 in the temporal cortex. The mRNA production of Lcn2, S100a10, Gbp2, Ptx3, Nlrp3, Il1b, Il1rn and Tgfb1 increased in all structures. Administration of anakinra reduced the gene expression of Il1b. Among the markers of microglia polarization, downregulation of Arg1 expression in the dorsal hippocampus and Nos2 expression in the temporal cortex was detected. Anakinra administration enhanced the decrease in Nos2 expression and restored the level of Arg1 expression to control values. Thus, anakinra administration did not affect the intensity of glial cell reactivation, but improved M2 reactivation of microglia.



Activated Endothelium Changes The Activity Of Multipotent Mesenchymal Stromal Cells During Physiological Hypoxia Or Short Hypoxic Stress In Vitro
Аннотация
Multipotent mesenchymal stromal cells (MSCs) are used for supplemental therapy of ischemic and inflammatory diseases. After systemic administration, transmigration of MSCs to the target tissue is accompanied by interaction with activated endothelial cells (ECs) at the site of injury. In this study, we investigated the influence of TNF-α-activated ECs on the functions of MSCs under different levels of hypoxia. For this purpose, MSCs and TNF-α activated ECs were cocultured in a direct cell-to-cell setting for a short period of time. MSCs retained their stromal phenotype and multilineage differentiation potential after interaction with activated ECs. At the same time, changes in molecules involved in MSC-cell and MSC-extracellular matrix interaction were detected. The paracrine activity of MSCs and activated ECs after interaction was demonstrated by both upregulated transcription and increased levels of pleiotropic IL-6 and IL-8. Proteases/antiproteases profiles were also altered after interaction. These data suggest that short-term interaction of MSCs with activated ECs may play an important role in tissue repair and remodeling processes. In particular, it may promote the migratory phenotype of MSCs. In comparison to physiological hypoxia – 5% O2, acute hypoxic stress (0.1% O2, 24 h) attenuated the stimulatory effects of ECs on MSCs.



Effects of Cold on the Adrenoreactivity of the Rat Superior Mesenteric Artery
Аннотация
In experiments on segments of the rat superior mesenteric artery (SMA) under isometric conditions, the effect of cold on the reactivity of this artery, estimated by the magnitude of the contractile reaction of its segments to noradrenaline (NA) at a concentration of 0.01–10.0 µM, as well as to electrical field stimulation (EFS) of perivascular nerves with a frequency of 3, 10 and 40 Hz in the absence and presence of NA in the medium and at a temperature of 37 oC or 25 oC was studied. Cooling was found not to change the tone of the SMA caused by NA at all the concentrations used. In the absence and presence of NA at a low concentration (0.01–0.10 µM), cooling leads to a significant decrease in the neurogenic response of the SMA at all frequencies of EFS, while in the presence of NA at a high concentration (1–10 µM), cooling has no statistically significant effect on this response. In the presence of NA at a low concentration, cooling at low EFS frequencies insignificantly, and at high frequency significantly reduces the potentiating effect of NA on neurogenic contraction of SMA. NA at a high concentration under normal temperature conditions, reduces the neurogenic contraction at all EFS frequencies, while under cooling conditions at low frequencies it has a potentiating effect, and at high EFS frequency it has a depressing effect. The results obtained show that the depressing effect of cold on the neurogenic constriction of the rat SMA, observed at low and disappearing at high concentrations of NA, as well as on the NA-evoked potentiation of the neurogenic vasoconstriction, is not associated with a decrease in the contractile effect of NA, which is the main neurotransmitter in this artery. These effects can contribute to the redistribution of blood from the surface deep into the body, thus reducing heat loss and improve thermoregulation.



Analysis of the State of Glutamate- and Gaba-Ergic Neurons in the Inferior Colliculi of Krushinsky – Molodkina Strain Rats at Early Stages of Epileptogenesis
Аннотация
Disturbances in the neurotransmitter systems during the development of temporal lobe epilepsy have been most detailed studied in forebrain structures – in the temporal cortex, amygdala, and hippocampus [1, 2]. It is known that during the formation of temporal lobe epilepsy in the model of audiogenic kindling there is a spread of epileptiform activity from brainstem to forebrain structures. However, the molecular mechanisms of neurotransmission dysregulation in the inferior colliculi in rodents with genetic prone to audiogenic seizures during epileptogenesis remain unknown. Changes in neurotransmitter systems of inferior colliculi may contribute significantly to the recruitment of forebrain structures during the initial stages of epileptogenesis.
The current work provides a comprehensive analysis of activity markers of glutamate- and GABA-ergic neurons in inferior colliculi of Krushinsky – Molodkina (KM) rats genetically prone to audiogenic seizures. A modified audiogenic kindling protocol was used to model the early stages of temporal lobe epilepsy development. In this protocol rats were subjected to daily audiogenic seizures for seven days. Naive KM rats were used as controls.
Although the rodent’s predisposition to audiogenic seizures is often associated with disruptions in GABAergic transmission, no significant changes were found in the expression of GABA synthesis enzymes or the α1 subunit of the GABAA receptor in the brains of KM rats, either 24 hours or a week after their last convulsive seizure. However, 24 hours after the last audiogenic seizure, an increase in glutamatergic transmission in the inferior colliculi was observed: the activity of ERK 1/2 kinases and the exocytosis protein synapsin 1 increased, as well as the expression of VGLUT1 and VGLUT2 and the synaptic protein SV2B. One week after the last seizure, only an increase in VGLUT1 content in the inferior colliculi was observed, suggesting that persistent changes occur in the neurons of forebrain structures, in particular, the temporal cortex.



Functional Changes in the Expression of the Aqp4 Gene in the Hypothalamus Under the Influence of Drinking Regimen and Arterial Hypertension in Rats
Аннотация
Aquaporin-4 (AQP4) is the main water channel in the central nervous system. AQP4 is densely expressed in brain structures suggesting a crucial role in water transport in normal conditions and in disease. The effect of changes in drinking regime (water-deprivation and hyperhydration) and inherited arterial hypertension on the expression of the AQP4 water channel gene in the hypothalamus, the center of regulation of visceral functions, was studied. It was shown that the level of the Aqp4 mRNA in hyperhydrated animals more than 1.5 times lower than in animals with water-deprivation. This decrease in the Aqp4 gene expression in the hypothalamus may be associated with the ability to prevent cytotoxic edema during increased fluid intake. Rats with inherited stress induced arterial hypertension (ISIAH) are characterized by an increased level of Aqp4 mRNA in the hypothalamus, which suggests the involvement of this channel in processes associated with the regulation of brain water balance during arterial hypertension and the prevention of vasogenic cerebral edema. Thus, the presence of the AQP4 water channel in the brain, associated with the protection of brain cells, is functionally determined by the state of the body. This may be evidenced by bidirectional changes in the Aqp4 gene expression during hyperhydration and arterial hypertension.


