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Obesity is a chronic multifactorial recurrent condition with serious health consequences that contributes significantly to the morbidity and mortality in the population. A positive energy balance, which occurs when food is consumed in an amount exceeding the energy consumption or when energy consumption is reduced, is considered one of the main mechanisms of obesity. The most common type of obesity is exogenous (alimentary-constitutional). There are various pathophysiological determinants of obesity, with adipose tissue playing the most significant role. Non-pharmacological therapies, including lifestyle changes through nutritional correction and increase in physical activity, behavioral therapies aimed at preventing or treating eating disorders, are recommended as the first, mandatory, and continuous stage of obesity treatment. However, the use of non-pharmacological interventions alone is often limited by insufficient effectiveness. Fonturacetam has a promising potential for use in the fight against obesity. The mechanisms of fonturacetam influence on body weight control, energy homeostasis, carbohydrate and fat metabolism, anorexigenic and anti-inflammatory effects showed in studies are the key factors determining the prospects of fonturacetam use in the complex therapy of obesity.

Purpose: to develop a model of the early stage of retinal neurodegeneration via an intravitreal injection of the dopaminergic neurotoxin. Material and methods. The experiment was carried out on 20 Chinchilla rabbits. The experimental groups received intravitreal injection of 0.1 ml of 6-hydroxydopamine (6-OHDA) in NaCl 0.9 % with 0.5 % ascorbate, containing 0.25 or 0.5 mg 6-OHDA. The control group received injections of 0.1 ml of NaCl-ascorbate solution without neurotoxin. On the 7th and the 14th days after the injection, intraocular pressure (IOP), pupillary light reaction and ocular blood flow were estimated and the fundus was examined. On the 7th day after an injection of 0.25 mg 6-OHDA, we used ELISA to measure dopamine concentration in retinal homogenates, while on the 14th day after an injection of 0.5 mg 6-OHDA, the concentrations of dopamine, norepinephrine, TNF-a and endothelin-1 were measured by the same method. Results. On the 7th day after a 0,25 mg injection of neurotoxine, we revealed a decrease of dopamine in the retina (0.043 ± 0.130 pg/mg protein compared with 0.10 ± 0,03 pg/mg protein in the controls, р < 0.01). On the 14th day, dopamine and norepinephrine levels showed a fourfold increase (р < 0.05). An injection of 0.5 mg of 6-OHDA caused a threefold increase of dopamine (р < 0.05) and a fivefold increase of norepinephrine (р < 0.01) concentration in comparison with the controls. On the 14th day, endotheline-1 level was 65 % higher than in the controls after a 0.25 mg 6-OHDA injection (р < 0.01) and 45 % higher after a 0,5 mg injection (р

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease. MS therapy does not always allow slowing of disease progression and also has significant side effects, such as immunosuppressive effects (especially when second-line disease-modifying therapies (DMT) are used). In this context, it is important to explore novel approaches to MS therapy that may improve the therapeutic potential of first line DMTs and reduce the likelihood of switching to switch to second line DMTs. Curcumin is one of the promising candidates for such application. Several anti-inflammatory and neuroprotective effects of curcumin have been reported in the literature, which could be considered for such applications. The favorable safety profile of this compound is also important. Over the past decade, encouraging clinical data have been obtained on the use of curcumin as part of adjunctive therapy for MS. However, to date, there are inadequate clinical studies on the use of curcumin in the therapy of MS. This may be due to the fact that curcumin, like other polyphenols, has low bioavailability, which limits its therapeutic potential. Recently, new highly bioavailable forms of curcumin have been developed (e.g., nanoemulsions). In this regard, it is promising to conduct new clinical trials of curcumin as an adjunctive therapy in MS, especially using its forms with increased bioavailability.

The leading role of neuroinflammation as the culprit of a long-term impairment of consciousness in patients after injuries to the central nervous system forces us to look for new effective strategies for resolving this pathological process. Xenon reducing the intensity of the inflammatory response due to the impact on several links is potentially able to have a beneficial effect on this category of patients. Using laboratory equipment, we evaluated the effect of half-hour daily inhalations of a 30% air mixture with 30% xenon for 7 days on the level of markers of neuronal damage and regeneration of nervous tissue.AIM To study the effect of inhalation of an air-xenon mixture on the dynamics of markers of neuroinflammation and restoration of nervous tissue in patients after traumatic brain injury (TBI).MATERIAL AND METHODS We conducted a prospective randomized clinical trial evaluating the effect of inhaled xenon for sedation on the level of consciousness and spasticity in patients with prolonged post-coma impairment of consciousness. Patients were randomized into 2 equal groups. In Group I (Comparison, n=15) in addition to the standard treatment for TBI, each patient included in the study underwent 7 sessions of inhalation of an air mixture with an oxygen content of at least 30 vol.% for 30 minutes. In Group II (Xenon, n=15) in addition to the standard treatment, each patient included in the study underwent a half-hour inhalation with an air-xenon gas mixture (with a xenon content of 30 vol.% and oxygen — 30 vol.%) for 7 days, 1 time per day. The levels of interleukin-6, α-1 acid glycoprotein (AGP), S100 b protein and brain-derived neurotrophic factor were assessed before the first treatment and then once a day for 6 days.RESULTS The final evaluation included 12 patients from the Comparison Group and 12 patients from the Xenon Group. The greatest difference in the concentration of interleukin-6 between the Comparison and Xenon Groups was noted on the 5th day - 12.31 (10.21; 15.43) pg/ml vs. 7.93 (3.61; 9.27) pg/ml, respectively; however, the findings only tended to be statistically significant (p=0.07). When assessing the AGP level, the maximum difference was noted on the 4th day. In the Comparison Group, the AGP level was 0.81 (0.74; 0.92) pg/ml versus 0.614 (0.4; 0.79) pg/ml in the Xenon Group. And again, the data showed only a trend towards statistical significance (p=0.09). The highest level of brain-derived neurotrophic factor in the Xenon Group was observed on the 3th day — 0.1271 (0.046; 0.2695) pg/ml, which was statistically significantly higher than the one in the Comparison Group — 0.062 (0.036; 0.121) pg/ml (p=0.04). The concentration of S100 b protein during the entire observation period in both groups did not exceed 0.005 pg/ml.CONCLUSION Xenon inhalation according to the method proposed by the authors had a beneficial effect on the processes of neural tissue regeneration, however, with regard to neuroinflammation, its effects were not so pronounced.

The review presents the results of clinical studies of the efficacy and safety of Tenoten and Tenoten children’s in the treatment of anxiety, neurotic, stress-related and somatoform disorders and adjustment disorders. Technologically processed antibodies to the S100 protein in Tenoten and Tenoten children’s drugs change the conformation of the S100 protein, which is considered as a pathological link in the development of anxiety states, as well as neurodegenerative diseases. Tenoten is a well-studied daytime anxiolytic that combines a favorable safety profile with high anxiolytic activity. The efficacy of Tenoten in the treatment of anxiety disorders is comparable to that of benzodiazepine drugs. Tenoten has no inhibitory and muscle relaxant effects, does not cause drug tolerance, addiction, "withdrawal" syndrome, as well as drug interactions. Tenoten for children has been shown to be effective in the treatment of anxiety in children, including those with somatic manifestations, attention deficit hyperactivity disorder, and learning disabilities.

Alzheimer's disease (AD) is the most common neurodegenerative disease and cause of dementia. It is associated with progressive cognitive decline due to the development of cortical and hippocampal atrophy. We reviewed key factors in AD pathogenesis, such as synaptic dysfunction, accumulation and aggregation of amyloid beta (A) peptide, tau phosphorylation causing neurofibrillary tangles, mitochondrial dysfunction, and neuroinflammation. We studied the dysbiosis role in AD development and demonstrated how much the bidirectional communication between the gut and brain sheds new light on some pathogenic processes underlying AD. We reviewed state-of-the-art biomedical technologies for studying AD: transgenic models, electrophysiological techniques, optogenetics, multi-omics approaches, neuroimaging, etc. New biomedical technologies significantly expanded our current knowledge of the AD pathogenesis and laid the groundwork for state-of-the-art treatment approaches.

Mental disorders often accompany autoimmune diseases, for example, since 1949 it has been known about “myxedematous madness”, a psychosis caused by hypothyroidism. The most common cause of hypothyroidism is Hashimoto's autoimmune thyroiditis. It is also known about another neuropsychiatric disorder associated with autoimmune thyroiditis, Hashimoto's encephalopathy. It is a severe dysfunction of the central nervous system, the pathogenesis of which is not associated with hormonal disorders. Cytokines are regulators and participants of inflammation, including autoimmune. Certainly, when we are talking about high concentrations cytokines, we mean systemic inflammation. The minimal or mediocre fluctuations in cytokines within the ranges that are characteristic of healthy status or normergic acute phase response in disease cannot be interpreted from the point of view of binary endocrinological logic. In the CNS, cytokines are able to influence on the neuroendocrine control of systemically regulated functions. It is also important that glial cells (astroglia, microglia) are capable of producing a number of cytokines and can affect neurons and develop behavioral changes. In addition, the ability of a number of cytokines outside the CNS itself to act on vagal afferents and through them to convey information to the CNS, affecting its state and functions, has been proven. It is reasonable to assume that minimal fluctuations in cytokine levels may also affect the state and function of the CNS. The aim of the study was to investigate the levels of cytokines in patients with thyroiditis; in patients with thyroiditis associated with mental disorders; in a group of healthy individuals; and evaluate the effect of cytokine levels on clinical manifestations. In the group of patients with thyroiditis and mental disorders, the levels of CCL20/MIP3α, IL-13, IL-2, IL-27, IL-5 were significantly higher than in other groups. At the same time, no positive correlation was found between the clinical manifestations of mental disorders and the levels of cytokines. A positive correlation was found between the levels of some cytokines and free triiodothyronine, as well as the level of antithyroid antibodies. Mental disorders associated with autoimmune thyroiditis may be associated with changes in the cytokine profile and result from neuroinflammation.

The development of new drugs to combat neuroinflammation is highly relevant as it opens up possibilities for the treatment of a wide range of diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, depression, and others. Kappa-opioid agonists represent a promising class of compounds with а high potential to be used in the treatment of neurological conditions accompanied by neuroinflammation.The aim of the study was to provide a summary of the current strategies employed to evaluate the neurotropic anti-inflammatory effects of kappa-opioid ligands in laboratory animals with induced neuroinflammation.Materials and methods. The databases, such as Google Scholar, PubMed, ScienceDirect, Scopus, e-Library were used as search tools. The search comprised the following keywords and phrases in Russian and English: kappa opioids + neuroinflammation; kappa opioid receptors + neuroinflammation; neuroinflammation models; neuroinflammation models in rats, neuroinflammation models in mice. 148 relevant articles were found, 122 were included in this review.Results. Various experimental models of neuroinflammation, including chemically-induced and bacterial endotoxin-induced neuroinflammation, as well as traumatic and genetic models in mice and rats were evaluated. In addition, the strengths and limitations of each model were critically assessed to identify the most appropriate and reliable approach for investigating the relationship between neuroinflammation and signaling pathways associated with kappa-opioid receptors.Conclusion. The neurotropic anti-inflammatory activity of kappa-opioid ligands have been comprehensively described. The review discusses both experimental models where the effects of kappa-opioid agonists have been investigated, as well as the models where the anti-inflammatory properties of kappa-opioid agonists have not been studied yet.

The article discusses the role of inflammatory reactions in the formation of attention deficit hyperactivity disorder (ADHD). Based on a wide and modern material, the mechanisms of development of oxidative stress with the formation of free radicals are considered, which, in turn, initiate a cascade of inflammatory reactions. Inflammation factors are analyzed in detail, biomarkers of neuroinflammation are distinguished and their role in changing the neurotransmitter balance is revealed. Biomarkers of neuroinflammation isolated from patients with ADHD give conflicting results in some particular issues, which certainly require clarification. But in general, it is found that increased inflammation in the early stages of brain development seems to be associated with the ADHD phenotype. ADHD is commonly believed to be a hereditary disease; therefore, it can be expected that patients have polymorphisms of genes associated with inflammation, which is illustrated in a wide range of material. In addition, the problems of inducing neuroinflammation with traditional drugs for the treatment of ADHD: methylphenidate and atomoxetine are considered. The prospects of developing algorithms for the diagnosis and treatment of attention deficit hyperactivity disorder are noted.

Head injury is one of the main disability causes among the working-age population. Stroke energy induces mechanical injury of tissues to launch secondary damage, i.e. neurotransmission, blood-brain barrier disruption, blood infiltration of brain tissues, cytokine and chemokine overexpression, and other processes. Activated by the injury, microglia plays a special part to initially 'protect' intact tissues from the products of necrosis and apoptosis. After the injury, microglia rapidly differentiates to phenotypes М1 and М2. Pro-inflammatory phenotype М1 produces neuronal cytotoxic cytokines including tumor necrosis factor-, interleukins (IL)-6 and IL-1, and NO that induce apoptosis while phenotype М2 secretes IL-4 and IL-13 that may supposedly reduce inflammation and improve recovery of brain tissues. М2 response lasts much less than М1 response, and increasing pro-inflammatory activation leads to further neuronal death, which affects cognitive and physical status of patients with head injury. The review covers main biochemical processes in the injured brain and possible ways of neuroinflammation modulation.

In addition to high mortality, craniocerebral injuries have another danger, a long rehabilitation period and a high percentage of disability with the development of cognitive impairment. This is primarily associated with the processes of neuroinflammation, which development, according to recent data, leads to a long-term impairment of consciousness. The anti-inflammatory effects of xenon inhalation anesthetic, which have been repeatedly shown in previous studies, have the potential to beneficially affect the level of consciousness in these patients by targeting key links of neuroinflammation.AIM OF STUDY To evaluate the effect of oxygen-xenon mixture inhalation on the level of consciousness recovery and the severity of spastic activity in patients after traumatic brain injury.MATERIAL AND METHODS A prospective randomized clinical trial of the effect of inhaled xenon sedation on the level of consciousness and spastic activity in patients with post-coma long-term impairment of consciousness was conducted. Patients were randomized into two equal groups. In group I (comparisons, n=15) (in addition to the standard treatment after a traumatic brain injury), each patient included in the study underwent 7 sessions of inhalation of an air-oxygen mixture with an oxygen content of at least 30 vol% for 30 minutes. In group II (study, n=15) (in addition to standard treatment), each patient included in the study inhaled an oxygen-xenon gas mixture (xenon content 30 vol%) for 7 days 1 time per day. Before and after the course of treatment (on the 7th day), patients were assessed using the CRS-R scale and the modified Ashworth scale.RESULTS The final evaluation included 12 patients from the comparison group and 12 patients from the study group. Three patients were excluded from each group as a result of critical incidents not related to the type of the therapy. In the comparison group on the 7th day, the level of consciousness was score 9 [7; 11] and did not differ statistically significantly from the baseline (p>0.05), which was score 8 [6; 10]. Spastic activity also did not change statistically significantly. In group II, the initial level of consciousness was 9 [7; 10], and on the 7th day — score 15 [12; 17], which was statistically significantly higher both in relation to the level of consciousness by the 1st day (p=0.021) within the group, and in relation to it on the 7th day in group I (p=0.038). When comparing spastic activity on the 1st and 7th days, we did not obtain a statistically significant difference in any of the groups.CONCLUSION Our method of xenon inhalation made it possible to have a beneficial effect on the level of consciousness of patients after traumatic brain injury, but this did not affect the final level of spastic activity in any way.

Modern fundamental and clinical studies show that chondroprotector molecules (chondroitin sulfate – CS; glucosamine sulfate – GS) can be useful in the treatment of neuroinflammation and so-called "inflammageing" – chronic, low-grade systemic inflammation that stimulates the development of neurodegeneration, atherosclerosis, ischemia, osteoarthritis and other pathologies. The role of CS and GS in the central nervous system are evident in the context of the concepts of the tetrapartite synapse and perineuronal nets (PNNs). Molecular mechanisms of action of CS and GS on neuroinflammation include: 1) interaction with the CD44 receptor, leading to inhibition of the pro-inflammatory factor NFκB, antiatherosclerotic and anticoagulant effects; 2) direct contribution to the formation of the PNNs, which support the division and differentiation of neurons; 3) inhibition of Toll-like receptors; 4) antioxidant and neuroprotective properties through activation of the PKC/PI3K/Akt signaling pathway; 5) inhibition of matrix metalloproteinases. These molecular effects determine the neuroprotective properties of CS/GS in ischemia, neurodegeneration, and pain syndromes associated with neuroinflammation.

The study of glioneuronal apoptosis and neuroinflammation is extremely important for understanding the causes of epilepsy. Currently, the focus is on neuronal apoptosis and certain aspects of neuroinflammation, while glial apoptosis remains poorly understood.Objective: to evaluate neuronal and glial apoptosis in conjunction with neuroinflammation in the area of the epileptic focus in patients with focal drug-resistant epilepsy (DRE).Material and methods. Biopsy specimens of the cortex and white matter of the temporal lobe of the brain from 30 patients with focal DRE due to focal cortical dysplasia were studied. We evaluated pathological changes and structural signs of apoptosis, levels of apoptotic and pro-inflam-matory factors such as caspase-3, caspase-9, FAS, FAS ligand (FAS-L), tumor necrosis factor α (TNFα), p53, nuclear factor κB (NF-κB). Histological methods, transmission electron microscopy (TEM), immunohistochemical study (IHC), and Western blot (WB) were used. The comparison group consisted of 21 people without epilepsy and brain involvement.Results. In DRE patients IHC revealed the expression of active caspase-3 in single neurons (20% of cases) and in gliocytes of the cerebral cortex and white matter (100% of cases). TEM revealed ultrastructural signs of apoptosis in all cases in neurons and oligodendrocytes. The WB of the epileptic focus showed an increased expression of the apoptotic factors caspase-9, FAS, p53 and pro-inflammatory factors TNFα, NF-κB.Conclusion. The results obtained indicate the presence of associated apoptosis and neuroinflammation processes of in DRE. Glial apoptosis is actively involved in epileptogenesis. The main part of apoptotic glia is oligodendrocytes, which explains the well-known phenomenon of myelin damage in epilepsy. Along with neuronal apoptosis, oligodendrocyte apoptosis together with neuroinflammation forms a self-sustaining pathological focus, which contributes to the progression of the disease and the occurrence of relapses.

Mortality and disability rates in spontaneous intracranial hemorrhages remain high despite medical advances. In recent decades, much attention has been paid to neuroinflammation as a typical response to brain damage. Inflammation plays an important role in the acute and chronic phases of the disease. The relationship between plasma and cerebrospinal fluid cytokines, as well as the factors affecting their ratios, is currently not completely clear.The objective was to study the inflammatory response to spontaneous intracranial hemorrhage.Subjects and Methods. 59 patients aged 18 to 72 years (48 ± 6) were enrolled in the study. Patients were admitted to the intensive care unit after an episode of spontaneous intracranial hemorrhage. The levels of interleukins in blood plasma were studied: 6, 8, 10, TNF-α, C-reactive protein,blood leukocytes, and procalcitonin (by a semi-quantitative method). In the cerebrospinal fluid, the following parameters were evaluated: cytosis, protein, glucose, lactate, cytokines (6, 8, 10, TNF-α). Blood samples were collected on days 1, 2, 3, 5, 7, 9, 14, 21, 28, 35, and 45.Results. Systemic inflammatory response developed in all patients from the first day of acute brain injury. The most significant response was formed by glial brain cells which was confirmed by high levels of cytokines in the cerebrospinal fluid, hundreds and thousands of times higher than blood levels of cytokines.Conclusion. Levels of pro-inflammatory cytokines are predictors of an unfavorable outcome.

Reduction of intraocular pressure is currently considered as the main strategy to stop or slow down the progression of glaucomatous optic neuropathy. However, this goal is achieved in only 1 in 7 patients with primary open-angle glaucoma (POAG). Therefore, it is important to determine further risk factors that can be therapeutically influenced. One example of such risk factors is lipid metabolism disorders. Material and methods. Literature search in PubMed using the queries “primary open-angle glaucoma” and “dyslipidemia” limiting oneself to the period from 2000 to 2021. Results. POAG is currently considered to be a systemic neurodegeneration with neuroinflammation at the forefront. Oxidized low density lipoprotein (oxLDL) acts as a free radical (so-called bioactive lipid) with pro-inflammatory properties and promotes glaucomatous neuroinflammation. Conclusion. In addition to a personalized targeted pressure-oriented intraocular pressure reduction, LDL-associated lipid metabolic disorders should be corrected in every POAG patient. LDL cholesterol below 100 mg/dl (2.6 mmol/l) in the blood is the critical threshold level.

Neurotoxicity is one of the common side effects of anticancer chemotherapy. This pathology has a detectability of 38–90%. In some cases, it causes not only a significant decrease of life quality but also decrease of dose of cytostatics. Therefore, the tasks of early diagnosis, prevention and treatment of neurotoxicity are very relevant. Sensors underlying detection, especially neuroinflammation processes, are needed to develop an effective therapy for chemotherapy-induced neurotoxicity. The purpose of this topic is to study the results of chemotherapy studies on changes in the activity of proinflammatory cytokines. In this regard, the study of behavioral societies in neuropathic pain in animal models is of great importance. It was revealed that various manifestations of inflammation of pro-inflammatory cytokines, chemokines, damage to the dorsal ganglion or distal nerve endings are increasingly being detected. Detection of chemically induced peripheral neuropathy using animal models is necessary for in-depth identification of the cause-and-effect mechanisms of its development and selection of new, more effective methods of treatment.

Introduction. In the structure of the total mortality of the population, cerebral stroke ranks second and leads among the causes of disability. Despite the huge number of patients with diabetes and stroke, the mechanisms underlying this predisposition remain poorly understood. Morphological changes of the brain in diabetes-induced neuroinflammation are practically not described anywhere.Objective. To establish the patterns of pathomorphological changes of the brain associated with neuroinflammation in patients with type 2 diabetes mellitus who have suffered a stroke.Materials and methods. On the sectional material, changes in the brain and arteries were studied in 27 stroke deaths (6 men and 21 women), aged 60 to 97 years, average age 75 ± 7.2 years, who had type 2 diabetes mellitus, the comparison group consisted of 32 stroke deaths (14 men, 18 women) with dyscirculatory encephalopathy without type 2 diabetes aged 42 to 100 years (average age 68.5 ± 14.2 years). Light-optical and electron microscopic examination of the brain, immunohistochemical reactions were performed: indirect immunoperoxidase reaction with gliofibrillary protein, vimentin and macrophage immunophenotyping markers – CD-68, CD-163, CD-21, CD-23, CD-11c, HAM.Results. It has been established that neuroinflammation is characterized by macrophage-microglial activation, penetration of antigen-presenting cells through the damaged blood-brain barrier, damage to neuronal and glial cell pools. Pronounced macrophage infiltration was revealed using immunohistochemical methods of investigation with CD-68. Monocytic macrophages and antigen-presenting cells are located perivascularly, migrating through the damaged blood-brain barrier and expressing the CD-11c receptor. There is a phenomenon of changing the phenotype of macrophages from M2-type, with sanogenetic activity, to M1-type, responsible for inflammatory damage.Conclusions. Pronounced infiltration of brain tissue in stroke patients with type 2 diabetes mellitus by both resident macrophages and monocytic macrophages is associated with progressive neuroinflammation.

The aim: analysis of literature data concerning the study on the relationship between changes in the composition, metabolic activity of the intestinal microbiota and the development of neuropsychiatric disorders and diseases. Results. Despite the different etiopathogenesis and clinical manifestations, neuropsychiatric disorders and diseases share common pathogenetic links: intestinal dysbiosis with depletion of microbial diversity, an increase in the representation of “pro-inflammatory” taxa and changes in the metabolism of the intestinal microbiota; damage of the mucosal barrier and increased permeability of the intestinal wall; immune response activation with the development of systemic inflammation and neuroinflammation; impairment of the nervous, endocrine and metabolic mechanisms of signal transmission within the gut-brain axis. Specific changes in the composition and metabolic activity of the intestinal microbiota act as biomarkers or additional diagnostic criteria at some neuropsychiatric diseases. Therapeutic approaches aimed at correcting the composition and metabolic activity of the intestinal microbiota: fecal transplantation, the use of psychobiotics and neuroactive derivatives of probiotic bacteria demonstrate a positive effect. Conclusions. The mechanisms of the specific microorganisms and their derivatives for influencing the functional activity of the central nervous system require further study. The gut microbiome should be considered as a target organ in the diagnosis and treatment of neuropsychiatric disorders and diseases. The microbiome-based approach contributes to early diagnosis and prediction of the clinical course severity. Targeting the correction of the intestinal microbiota composition and functional activity is a promising strategy for increasing the effectiveness of the neuropsychiatric pathology treatment.

Introduction. T cells play a significant role in neuroinflammation in Parkinson's disease (PD). Gamma delta T cells are an under-researched 'minor' subpopulation of T cells. An assessment of the immune system in patients with PD, with a focus on Т cells, provides new data on the pathogenesis of neurodegenerative diseases. The aim of the study was to examine the lymphocyte subpopulations, nonclassical Т cells, as well as cytokine production in patients with 3 stage PD complicated by motor fluctuations. Materials and methods. We examined 20 patients with 3 stage PD receiving dopaminergic combination therapy (main group) and 20 age-matched patients with chronic cerebrovascular disease (comparison group). Considering the suspected role of chronic constipation in maintaining dysbiosis and chronic inflammation in patients with PD, the presence of constipation was an inclusion criterion for this study. The subpopulation profile of the peripheral blood lymphocytes was assessed using flow cytofluorometry, as well as cytokine levels using enzyme linked immunosorbent assay. Results. It was found that the number of mature CD3+ T cells with or chains as the T-cell receptors (TCR) in the lymphocyte population was significantly lower in patients with PD median 74% (57.383.5)) than in the comparison group (median 80% (73.086.0); р = 0.014. There was also a statistically significant reduction in the number of CD3+CD56+ natural killer (NK) T cells in the group of patients with PD vs. the comparison group 4.7% (1.37.7) vs. 7.8% (0.824); р = 0.036. At the same time, the number of CD3CD56+ NK cells was significantly higher in the group of patients with PD (16.4% (934)) vs. the comparison group 8.7% (515); р = 0.001. Moreover, the main group had a statistically significantly higher number of activated CD3CD8+ NK cells 7% (4.513.5) vs. the comparison group 3.5% (0.864.9); р 0.001. Out of the total number of Т cells, the TCR CD4+CD8 subpopulation was statistically smaller in the group of patients with PD 13.6% (6.227.0) than in the comparison group 29.8% (4.052.1); р = 0.016. The study of cytokine levels in the group of patients with PD showed a significant increase in the induced production of interleukin-1 (IL-1), as well as a high (aberrant) spontaneous production of IL-10, which was 227.5 pg/ml in patients with PD when the normal range is 023 pg/ml. The correlation analysis showed that the TCR CD4+CD8 subpopulation and cytokines in the group of patients with PD had a statistically significant (p = 0.048) negative correlation with the induced production of IL-10 (r = 0.745) and a significant (p = 0.042) positive correlation with the induced production of the pro-inflammatory cytokine IL-1 (r = 0.648). There was a trend towards increased spontaneous production of IL-10 (r = 0.602; p = 0.0506) as the level of the TCR CD4+CD8 T helper cells decreased. Conclusion. Changes were found in the blood of patients with PD, which indicate a chronic inflammatory process: increased number of CD3CD56+ NK cells, including activated CD3CD8+ cells, and increased production of pro-inflammatory cytokine IL-1 and anti-inflammatory cytokine IL-10. A decrease was found in the level of a minor subpopulation of T cells, TCR CD4+CD8. The correlation found between this subpopulation and the production of pro- and anti-inflammatory cytokines indicates its role in regulation of chronic inflammation in PD.

Aim. To study markers of blood-brain barrier dysfunction (BBB) in patients with pharmacoresistant epilepsy (PhRE) – the amount of VEGF in endotheliocytes of brain capillaries, TNF-α in brain tissue and cytokine profile in blood serum.Materials and methods. The study included 30 patients with PhRE who underwent anterior temporal bloc resection. Histological samples of the brain were examined to assess the amount of VEGF and TNF-α; the concentration of cytokines in the blood serum was determined.Results. In the PhRE group, the densitometric density of cells expressing VEGF and the amount of TNF-α in the epileptogenic focus were higher than in the control groups (p < 0.001; p < 0.05). Compared with the control, the serum concentrations of IL-2 (0.98 ± 0.28 pg/ml vs. 2.80 ± 0.71 pg/ml; p < 0.001), IL-8 (14.04 ± 1.46 pg/ml vs. 26.13 ± 3.80 pg/ml; p < 0.001) and EGF (43.72 ± 5.63 pg/ml vs. 83.62 ± 24.06 pg/ml; p < 0.05) were statistically significantly lower in the PhRE group, and the amount of TNF-α (33.09 ± 1.23 pg/ml vs. 24.85 ± 1.32 pg/ml, p < 0.05), IL-4 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml, p < 0.05), IL-5 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml; p < 0.05), IL-7 (16.65 ± 3.07 pg/ml vs. 8.13 ± 1.67 pg/ml; p < 0.05), GRO (growth-regulated protein) (3054.0 ± 200.8 pg/ml vs. 1367.0 ± 187.3 pg/ml; p < 0.001), VEGF (316.10 ± 55.28 pg/ml vs. 95.22 ± 15.78 pg/ml; p < 0.01) are statistically significantly higher. There were no significant differences in the concentration of IL-1β, IL-1RA, IL-10 and IFN-γ between the PhRE group and the control.Conclusion. Based on the studied cytokine profile, there is no systemic inflammation in patients with PhRE. The established overexpression of VEGF in the brain and an increase in its concentration in the blood, combined with a decrease in serum EGF concentrations and an increase in GRO, as well as pro-inflammatory factors, indicates damage to the BBB. A high amount of TNF-α in the epileptic focus indicates neuroinflammation, and an increased concentration of this marker can be found in the blood of patients with BBB dysfunction.

SARS-CoV-2 infection leads to severe multiple organ failure. The immune system is stimulated by activating the inflammatory mechanism and by releasing inflammatory cytokines. COVID-19 is able to penetrate the central nervous system, inducing neuritis and neurodegeneration. In our study, we analyzed the latest available articles. We focused on the subject of COVID-19 infection and consequences of neuroinflammation. For this study, we searched the literature available in Pubmed and Google Scholar databases using keywords. There is evidence of a common background of COVID-19 complications and neurological diseases such as Parkinson's or Alzheimer's disease. This type of complication is more frequently observed in serious cases of COVID-19, with a more intense immune response, with higher levels of CRP, ferritin and D-dimers. Organic changes in conjunction with environmental stress caused by the experience of severe illness, fear of becoming ill and social limitations, lead to neuropsychiatric pathologies, including major depressive disorders and post-traumatic stress. The neuropsychiatric implications of COVID-19 represent a severe clinical problem that deserves special attention in the treatment of COVID-19 infection. There is a need to monitor the neuropsychiatric consequences of COVID-19, in order to completely understand the impact of SARS-CoV-2 infection. This knowledge is necessary to be able to confront the public health crisis created by the COVID-19 pandemic.

Abstract Introduction and purpose: Ketogenic diet (KD) is a form of nutrition based on usage of ketone bodies, received from transformation of consumed fats as a main source of energy. Advantages of this type of metabolism are used in treatment of various diseases. Our purpose is to sum up and present what we know about its usage, as a therapeutic tool, so far. Description of the state of knowledge: The use of ketone bodies, instead of glucose, as a main source of energy is more efficient, reduces oxidative stress and inflammation. Furthermore, it modulates gut microbiota. KD is used in the treatment of drug-resistant epilepsy in children and is proved to be useful in the treatment of type 2 diabetes. It can improve health of patients with non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases and psychiatric diseases. The usage in other areas is still under research. It is also necessary to take into consideration adverse effects of KD such as an increase in level of LDL-cholesterol and a potential lack of some macro- and microelements. Additionaly, maintaining the diet seems to be difficult, therefore, there is no enough data to fully describe its impact on human health in long-term perspective. Conclusions: The findings presented in this paper suggest that a ketogenic diet can constructively supplement the treatment of drug-resistant epilepsy in children and aid the treatment of type 2 diabetes. Regarding diseases associated with oxidative stress and inflammation, the reviewed data indicates that KD could be of use. However, KD is not recommended to be routinely ordered before further studies have substantiated and observable effect.

Traumatic brain injury is one of the main causes of both acute and long-term morbidity that concern that affects individuals in all demographics. The processes that occur during traumatic brain injury and neuroinflammation cannot be fully explained in most clinical and preclinical researches.Neuroinflammation is a very complex interaction between the cells of the innate and adaptive immune systems. The development of reactions of the innate immune system occurs under the influence of various signals that are released from damaged cells and tissues. This leads to the activation of neutrophils, microglia and astrocytes, the release of complement, as well as the release of histamine by mast cells.Subsequently, activation of an adaptive immune response leads to the development of later effects of neuroinflammation. The topic of biomarkers in traumatic brain injury is extensive and rapidly developing. We presented an overview of the most common and well-studied biomarkers in the literature regarding head injury in humans and their role in predicting the outcome in traumatic brain injury. Among the presented biomarkers, the most specific for traumatic brain injury are interleukins-6, -8, -10 and matrix metalloproteinases. We can use interleukin-6 to predict the outcome and risk of complications of traumatic brain injury. The concentration of interleukin-8 shows the relationship of the biomarker with mortality. We can use interleukin-10 to confirm the results of computed tomography in traumatic brain injury. Matrix metalloproteinases present the degree of violation of the blood-brain barrier and brain dysfunction. Other indicators need a more complete study to clarify their role in this pathology. Of course, for a more reliable conclusion about the patient›s condition, it is preferable to use the data of several biomarkers at the same time.

Recent studies have provided strong evidence that long-term ethanol consumption leads to activation the mechanisms of neuroimmune signaling. Recently, much attention has been focused on the study of toll-like receptors (Toll-like receptors, TLRs), which play one of the key roles in the mechanisms of activation of the innate immune system in brain structures subsequently ethanol consumption. It is known that the activation of TLRs leads to the release of many proinflammatory cytokines with the resulting neuroinflammatory process. There are suggestions that TLRs may also be involved in the modulation of neurotransmitter systems of the brain, thereby contributing to the formation of pathological dependence on ethanol. The goal of our work was to study the level of expression the genes of TLRs (TLR3, TLR4, TLR7) and pro-inflammatory cytokine genes (IL-1β, CCL2) in the rat brain (amygdala, hippocampus, medial entorhinal cortex, striatum) under conditions of prolonged alcoholization and on different periods of alcohol withdrawal, which was previously not studied by researchers. Prolonged alcoholization of rats with ethanol did not lead to changes in levels mRNA of TLRs in the studied structures of the rat brain, with the exception of a small increase in the level of TLR3 mRNA in the hippocampus of prolonged alcoholized rats and a slight increase in the level of TLR3 mRNA in mEC. However, gene expression of TLRs undergoes changes in all the structures of the rat brain studied by us at different periods of alcohol withdrawal. The increased level of expression of both TLRs and proinflammatory genes in the period of alcohol withdrawal in the rat brain hippocampus deserves special attention, which indicates the presence of a persistent neuroinflammatory process in this brain structure in the period of alcohol withdrawal, which is probably supported with the participation of TLR-dependent signaling. The study of the mechanisms of inflammatory process activation by TLR-dependent signaling in different brain structures can open new targets for drug exposure. Such drugs can be used in the treatment of alcoholism.

The authors reviewed the literature and presented results of their own research of post-operative cognitive dysfunction confirming its social importance. The development of post-operative cognitive dysfunction is to be perceived as a real fact despite the differences in the published epidemiological data. Currently, there are no grounds to correlate it directly with the general anesthesia given to patients, and there is no evidence that a certain method of anesthesia or a certain drug can reduce the frequency of post-operative clinical decline. There are numerous factors within genesis of post-operative cognitive decline and they are not studied well. All suspected mechanisms (neurotoxicity of the used agents, and other factors of anesthesia and surgery; impairment of information neuro-transmission mechanisms; neuroinflammation developing as a response to trauma) can initiate the complex neuro-physiological reactions causing cognitive dysfunction.The authors presented experimental data about morphofunctional changes in neurons and cerebellar cortex microglia after laparotomy and anesthesia with sevoflurane followed by the exposure to it in a special box for 6 hours (induction of 8 vol. % with the air flow of 2 l/min., maintaining 2 vol. % of sevoflurane with the air flow of 1 l/min.). They demonstrated that neuroinflammation was not the key factor of the detected neuronal damage. Purkinje neurons were damaged the most, since they were fairy sensitive to energy metabolic disorders, promoting the death of other neurons of the molecular layer. Neurons of the granular layer with the low level of energy metabolism were the most resistant to the impact provided by surgery/anesthesia. These data confirmed the importance of multifactorial approach when assessing the genesis of cognitive dysfunction. This research is to be continued and aimed to find out predictors of post-operative cognitive decline and to optimize anaesthesiologic support of surgery and other invasive interventions to provide a balance between their aggressiveness and effectiveness of protection, especially in senile patients who already have some cognitive dysfunctions.

Neuroinflammation may be involved in the development of neurodegeneration in Parkinson's disease (PD). Objective. To study the possibility of obtaining a morphologically confirmed model of parkinsonism syndrome in rats after 30 days of intranasal (i/n) administration of Lipopolysaccharide (LPS) Escherichia coli. Material and methods. Experiments were carried out on male rats of the Wistar line. Animals of the main group (n=7) were injected i/n LPS at a concentration of 1 μg / ml, and the control group (n=7) was administered water for injection daily for 30 days. Thirty days after the start of the experiment, the brain was taken for morphological examination. Results. No differences in the motor activity of the rats in the main and control groups were detected. Expressed neurodegenerative and inflammatory changes of the black substance, which spread to the area of the striatum, were found. Conclusions. The neuroinflammatory model of the premotor stage of Parkinson's syndrome was obtained.

Introduction. Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) with a predominant lesion of the compact part of the substantia nigra and the death of dopamine-producing neurons. Methods. Retrospective analysis of our database, as well as the study of foreign publications. Results. Recent studies of the etiology of PD indicate the possible role of viral and bacterial infections which are neurotropic in the development of the disease. Conclusion. The available data indicate that the etiopathogenesis of PD is multifactorial. The term “neuroinflammatory penumbra” can be used to describe the contribution of inflammatory responses to disease. A promising area for development may be new therapies that affect inflammatory responses in the nervous system. [ABSTRACT FROM AUTHOR]

Over the past decade, there has been a large amount of evidence indicating neuroendocrine, biochemical, and immune disorders in many acute and chronic central nervous system (CNS) diseases, including epilepsy, which made the authors consider the inflammatory theory of epileptogenesis. The chronic inflammatory process in epilepsy is believed to be facilitated by the activation of microglia and astrogliosis, which are accompanied by neuronal damage. The main postulate of this type of investigation is the assumption that the basis for CNS inflammation is blood-brain barrier (BBB) damage. Cytokines are presumed to play the greatest role in this process, mainly because they are natural pro- and anticonvulsants.Patients and methods. Examinations were made in 160 patients with epilepsy (drug-resistant epilepsy (n = 80) and controlled epilepsy (n = 80)) and 30 apparently healthy donors. The blood and cerebrospinal fluid (CSF) levels of the cytokines interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), IL-1 receptor antagonist (IL-1RA), soluble IL-2 receptor (sIL-2R), brain- derived neurotrophic factor (BDNF), S100b protein, С-reactive protein (CRP), and albumins were analyzed using a solid-phase enzyme-linked immunoabsorbent assay. Statistical analysis was performed using Student’s t-test and Mann-Whitney U-test. Differences at p

Hippocampus plays an important role in the cognitive mnestic functions. It coordinates emotional process, defines the intensity and specificity of behavioral, neuron and hormone reactions. Structural changes in hippocampus neurons can result in learning and memory disorders. The objective: to investigate morphometric parameters of hippocampus fields in rats after abdomen surgery with exposure to sevoflurane. Subjects and methods. The experimental research was performed using Wistar rats (n = 15). Rats from the experimental group (n = 7) had abdomen surgery with anesthesia with sevoflurane with the consequent continuous exposure to it (6 hours, 2 vol. % of sevoflurane, air flow – 1 l/min.). During 21 days rats from both groups had a number of behavioral tests. In 12 hours after the last behavioral test (on the 22-th day after the start of the experiment) the rats were decapitated with consequent brain extraction. The obtained materials were fixed in 10% neutral formalin on phosphate buffer (pH 7.4) for 24 hours minimum. Preparations of CA1, Ca2, Ca3, and Ca4 fields were studied under light microscope DM-750 (Leica, Germany) using the computer image analysis software of ImageScope M with 400-fold magnification. Results. The tests showed that cytoarchitectonics of hippocampus field was intact, pyramidal neurons had a large rounded nucleus with one, two or more distinct nucleoli. No pericellular and perivascular edema was detected. In the experimental group, all fields of the hippocampus had structural and functional changes. It manifested through both quantitative and qualitative signs of neuronal damage, especially in the Ca1 field. Segments of pyramidal neurons were disorganized, morphologically modified neurons were found: hyperchromatic shriveled neurons with no nucleus or poorly visible nucleus of the irregular shape. The appearance of morphologically changed neurons and disorganization of hippocampal layers led to changes in the width of pyramidal neurons segments. Conclusion. Morphological changes of hippocampal structures of rats after surgery and anesthesia may be the cause of cognitive functions decline during the postoperative period.

Delirium in the intensive care ward is actively being discussed by anesthesiologists for a long period of time. However at present there are fairly scarce evidences on the efficiency of various techniques of prevention and management of this disorder. Goal of the research: to assess the impact of inhalation sedation on the intensity and duration of sepsis-associated delirium in the intensive care ward of the surgical hospital. Methods. The one-centered, prospective, randomized comparative study was conducted in order to assess the efficiency of inhalation sedation in the patients with sepsis-associated delirium. Propofol was used for the intravenous sedation in the control group. 187 adult patients, admitted to the intensive care ward of Vorokhobov City Clinical Hospital no. 67, were included into the study. Results. Inhalation sedation reduced the delirium duration compared to intravenous use of propofol: delirium was fully managed on the 5th day in the group where sevorane was used [4; 7], while in the group where propofol was used delirium lasted for 7 days [6; 8] (p = 0.03). The study did not detect any effect of inhalation sedation on the intensity of oxidative stress (level of oxidized peptides in the blood plasma of the patients) and degree of neuronal damage (differences between groups are not significant, p = 0.37). No differences were recorded in the value of procalcitonin and SOFA score at any stage of the study. Conclusion. The frequency of delirium in the mixed population of sepsis patients makes 27.9%. Use of inhalation sedation with sevoflurane compared to intravenous administration of propofol reduces the duration of delirium therapy from 7 to 5 days.

Immune system plays a key role in pathogenesis of ischemic stroke. Ischemic brain injury causes destruction of cells and extracellular matrix proteins, and the release of „danger“ molecules that cause rapid activation of innate immunity, and induce adaptive autoimmune reactions. The cells of innate immunity are responsible for elimination of cellular and extracellular debris and tissue repair, being, however, involved in post-ischemic inflammation causing brain injury. An adaptive immune response which develops within a few days is directed against self-antigens, being not related to nervous tissue damage in acute phase of stroke. The cells of adaptive immunity are able to regulate microglial activity and promote repair processes in the central nervous system. However, long-term persistence of lymphocytes with reactivity for brain-derived antigens may be involved into the atrophy of cerebral cortex, and development of dementia in remote post-stroke period. Immune response following ischemic brain stroke is manifesting by local and systemic reactions. Nevertheless, in contrast to prolonged local intracerebral inflammation in infarction area, and peri-infarction region, a systemic inflammatory response is quickly replaced by development of immunosuppression, as evidenced by lymphopenia, lymphoid organ atrophy and defective functions of immune cells. Immunosuppression is largely due to activation of sympathoadrenal system, aiming for limitation of inflammatory and autoimmune reactions. However, excessive immunosuppression leads to development of infectious complications, which may often cause lethal outcomes, and also may have a negative impact on efficiency of repair processes. The present review provides experimental and clinical data describing the innate and adaptive immune reactions in response to cerebral ischemia. Moreover, this review discusses possible pathogenetic importance of immune cells and their positive or negative effects, thus allowing further development of new therapeutic approaches for treatment of ischemic stroke.

Introduction. Alzheimer's disease is a chronic neurodegenerative disease that leads to neuropsychiatric disorders and decrease in cognitive activity. A number of studies demonstrate the important role of the mitogen-activated protein kinase (MAPK) pathway and inflamasome NLRP3 in disturbing the metabolism of -amyloid and insulin resistance in Alzheimer's disease. Objective. To study the expression of NLRP3 on cells of neuronal and glial nature, as well as MAPK on neurons in the amygdala of animals with experimental Alzheimer's disease. Material and methods. Subjects of the study were: 1) CD1 mice (males, 4 months old) divided in 2 groups, the experimental group (intra-hippocampal intjection of -amyloid) and the control group (sham-operated animals); mice with a genetic model of Alzheimers disease, the B6SLJ-line Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas (males, 12 months old) and the corresponding control group, C57BL/6xSJL mice (males, 12 months old). Immunohistochemistry on free-floating sections was used to study the expression of NLRP3 and MAPK in the brain amygdala. Results. It was found that NeuN/NLRP3-positive cells were increased in animals with a genetic model of Alzheimer's disease in the amygdala (29.052.67) compared with the control animals (17.101.95) (p=0.043). A similar picture was observed in -amyloid-induced neurodegeneration (p=0.021). Intra-hippocampal injection of -amyloid caused the decrease of MAPK expression in the amygdala neurons (5.970.66) compared with sham-operated animals (13.252.65) (p=0.018). A similar situation was observed in animals with a genetic model of Alzheimer's disease (p=0.031). Conclusion. Increase of expression of inflammasomes NLRP3 was observed on neurons, but not astrocytes, in animals with experimental Alzheimer's disease. Wefound a decrease of the expression of MAPK on neurons in the amygdala. This indicates coupling of the inflammatory process and the disturbances of insulin-signaling mechanisms in the brain in neurodegeneration.

Mental illnesses in patients with sepsis occur in 23—32% of cases and are an unfavorable prognostic sign. At present, the causes of these disorders are adequately explained by the theory of neuroinflammation that takes into account the pathogenic influence of the systemic inflammatory reaction and related endothelial dysfunction on the central nervous system function.The purpose of the study was to evaluate the relevance of the severity of the systemic inflammatory response, the intensity of oxidative stress and the severity of patient's general state to prediction of the duration of delirium and therapy outcomes in patients with sepsis-associated delirium.Materials and methods. A pilot, single-center, prospective, cohort study was performed in 187 adult patients diagnosed with sepsis who were treated in the intensive care unit of L. A.Vorokhobov Municipal Clinical Hospital No. 67. The following tests and examinations were performed: Vasoactive-Inotropic Score (VIS), Sepsis-related Organ Failure Assessment score (SOFA), Intensive Care Delirium Screening Checklist (ICDSC); plasma levels of carbonylated peptides, procalcitonin (PCT), and neuromarkers were monitored; and a correlation analysis with the severity of the sepsis, its duration and therapy outcomes was performed.Results. A moderate correlation (R=0.68; P

Neurosteroids are endogenous modulators of nervous excitability. There is increasing evidence of sedative, anxiolytic, analgesic and anticonvulsant properties of neurosteroids. Progesterone and allopregnanolol participate in adaptation to stress, and also have immunomodulating activity and cytoprotective properties. Neurosteroids have the potential therapeutic possibilities associated with molecular mechanisms of the epileptogenesis interruption and modulation of neuroinflammation and neurogenesis in the brain.

Alcohol intake during pregnancy may affect the normal course of fetal development, leading to the formation of symptoms of fetal alcohol spectrum disorders (FASD). There is evidence that a number of prenatal pathologic conditions exhibit alterations in the regulation of expression mechanisms of several pro- and anti-inflammatory cytokines. In our study, we focused on examining the expression levels of a number of pro- and anti-inflammatory cytokine genes in the forebrain and temporal regions of rat brain during the postnatal developmental period when modeling prenatal alcohol exposure (PAE). We also evaluated the expression level of genes that are associated with the regulation of gene expression of pro- and anti-inflammatory cytokines. In addition, the objectives of our study included pharmacological correction of the observed changes by a potential pharmacological agent - rifampicin, which according to other studies had a neuroprotective effect. The PAE was modeled by mating pregnant female rats with a 15% ethanol solution throughout pregnancy. Injections were performed in rats from the 1st to the 7th postnatal days. Brain structures were sampled for gene expression analysis on the 8th postnatal day. The results of the study showed the presence of changes in the expression of Tlr3 and Tlr4 genes on the 8th day of postnatal development in the anterior and temporal lobes of the brain. The expression of Myd88 and Ticam genes had multidirectional changes among the studied brain structures of PAE rats. The increased mRNA level of proinflammatory genes was noted. The use of Rif in experiments showed the ability of Rif (50 mg/kg) to correct the observed long-term pathological changes in the expression of the genes under study. It is of interest to study the dose-dependent effect in the future, as well as to investigate the revealed changes by protein methods. In addition, it seems important in the future to study the TLR signaling system in other brain structures with PAE, as well as at different terms of postnatal development in ontogenesis.

Alzheimer's disease causes gradual, persistent deterioration of cognitive function in the elderly, causing social and economic damage to society. Over the past decades, mankind has made significant progress in the study of Alzheimer's disease, but there are no methods to fully control the disease. The lack of effectiveness of existing treatment methods emphasizes the need to search for new approaches. The present review is devoted to the study of the latest data regarding the role of microbiota in the mechanisms of formation and progression of Alzheimer's disease, possible therapeutic ways to influence the processes of neurodegeneration through microbiota and taking into account identified relationships. The article considers the axis «gut microbiota-brain» as a link in the pathogenesis of neuroinflammation. New data on the influence of gut microbiota on neurodegenerative processes through metabolic, nervous, and immune mechanisms is analyzed. New data reveals correlations between microbiota specifics and the origin and/or progression of Alzheimer's disease, expanding the understanding of disease pathogenesis. The role of the oral microbiota in neurodegeneration processes is mentioned, emphasizing the diverse mechanisms of this disease. Available therapies for Alzheimer's disease are discussed, including probiotics and prebiotics, fecal microbiota transplantation, and dietary correction.

The article examines the potential role of brain mechanical damage as a trigger for the development of neurodegenerative changes. Attention is paid to dysfunction of the neurovascular unit, and disruption of the functional and compensatory capabilities of blood flow. The importance of microhemorrhages that occur in the acute period of injury and the formation of first focal and then diffuse neuroinflammation is emphasized. The importance of mitochondrial dysfunction was separately determined as a significant factor in increasing the risk of developing Alzheimer's disease (AD) in patients after traumatic brain injury (TBI). In TBI, there is a decrease in the expression of tight junction (TC) proteins of endothelial cells, such as occludin, claudin, JP, which leads to increased permeability of the blood-brain barrier. TBI, provoking endothelial dysfunction, contributes to the development of metabolic disorders of β-amyloid and tau protein, which in turn leads to worsening vascular damage, resulting in a vicious circle that can ultimately lead to the development of AD and dementia. Age-related changes in cerebral arteries, which impair perivascular transport of interstitial fluid, are currently considered as an important part of the «amyloid cascade», especially against the background of genetically mediated disorders of glial membranes associated with defective aquaporin-4 (encoded by the APOE4 ). Studies in animal models of TBI have revealed an increase in tau protein immunoreactivity and its phosphorylation, which correlates with the severity of injury. A comprehensive analysis of research results shows that the cascade of reactions triggered by TBI includes all the main elements of the pathogenesis of AD: disorders of energy metabolism, microcirculation and clearance of cerebral metabolic products. This leads to a disruption in the metabolism of amyloid protein and its accumulation in brain tissue with the subsequent development of tauopathy. Cerebrolysin, by modulating the permeability of the blood-brain barrier, blocks the development of neuroinflammation, reduces the accumulation of pathological forms of proteins and may be slow down the progression of neurodegeneration.

Post-traumatic stress disorder (PTSD) is a common mental health disorder, with an incidence of up to 12.5% among primary care patients. Most often, PTSD is detected in combat veterans, victims of terrorist attacks and terror, but it can also be a consequence of traumatic brain injury and medical interventions. Impaired cognitive functioning is a key feature of PTSD, including attention deficits and reduced processing speed, executive dysfunction, and impairments in verbal learning and memory. Cognitive impairments in PTSD are significantly persistent and are largely similar in nature to neuropsychological impairments in neurodegenerative pathology. Possible pathogenetic mechanisms underlying PTSD are the development of neuroinflammation, oxidative stress and decreased production of neurotrophic factors. One of the promising areas of treatment is the use of Cerebrolysin, which has powerful neurotrophic and anti-inflammatory activity.

In recent years new data have been obtained on the role of intestinal dysbiosis in the pathogenesis mechanisms of neuroinflammation and neurodegeneration in Alzheimer's disease (AD), as well as on the influence of dietary patterns (Mediterranean diet, MIND diet) and probiotics on the correction of dysbiosis and slowing down the development of cognitive disorders. It seems reasonable to draw the attention of practicing physicians to the need to prevent cognitive dysfunction through dietary correction, probiotics and prebiotics intake. The purpose of the research was to study the possibility of using certain dietary patterns, as well as intake of probiotics and prebiotics for the correction of dysbiosis and early prevention of cognitive dysfunction, basing on the analysis of published data on the bidirectional communication between the colon microbiota and the brain and microbiota changes in patients with cognitive dysfunction and AD. Material and methods . We searched domestic and foreign literature devoted to gut microbiota, the "gut-brain" axis, microbiota disorders in AD patients; mechanisms of neuroinflammation and neurodegeneration; the role of dietary patterns, in particular MIND diet, pre- and probiotics in the prevention of cognitive dysfunction - via PubMed search engine, SemanticScholar Google Internet search platform and domestic scientific electronic library Cyberleninka. 72 literature sources were analyzed. Results . Intestinal dysbiosis and disruption of intestinal barrier integrity play an important role in the pathogenesis of neuroinflammation and neurodegeneration. Changes in the microbiota in patients with cognitive impairment and AD are associated with disease severity and are generally characterized by increased numbers of Gram-negative microorganisms in Bacteroidetes and Proteobacteria phyla and decreased numbers of Gram-positive microorganisms in Firmicutes and Actinobacteria phyla. An increase in gram-negative microorganisms abundance leads to elevated release of lipopolysaccharides (LPS) that disrupt the integrity of the intestinal mucous barrier and, through a series of steps, initiate neuroinflammation. Course application of probiotics containing representatives of Bifidobacterium and Lactobacillus genera, in particular, Bifidobacterium breve A1 и Lactobacillus plantarum С29 strains, leads to improved cognitive function, which can be explained by anti-inflammatory and antioxidant effects. Long-term prospective studies of the effects of dietary patterns such as the Mediterranean diet and the MIND diet clearly show delayed regression of cognitive function in older adults without initial dementia as well as in patients with AD. For example, according to various studies, individuals who have strictly adhered to the Mediterranean diet for 6-9 years have a 23-39% lower risk of developing cognitive impairment. Adherence to the MIND diet for 6 years has a statistically significant association with higher verbal memory scores. Correction of gut dysbiosis, including through the administration of probiotics, prebiotics and bringing the diet to the MIND diet pattern, is the most affordable and rational method for early prevention of cognitive dysfunction. Conclusion . A promising strategy in the early prevention of neuroinflammation, cognitive impairment and dementia is to maintain the balance of the gut microbiota. The solution to this problem is achieved by adjusting the dietary pattern, increasing the use of dietary fiber and prebiotics and reasonable use of probiotics., Competing Interests: The authors declare no conflicts of interest., (Copyright© GEOTAR-Media Publishing Group.)

Objective: Evaluation of the efficacy and safety of the use of the drug Miladean in the treatment of patients with cognitive disorders (CDs) of vascular genesis., Material and Methods: In during the double-blind multicenter prospective randomized placebo-controlled phase III clinical trial, 300 patients with CDs and chronic cerebral ischemia were randomized into 3 groups: group 1 ( n =100) received Miladean (daily dose: memantine 10 mg + melatonin 6 mg), group 2 ( n =101) - memantine (10 mg/day), group 3 - placebo ( n =99) for 8 weeks. The dynamics of the overall score (the primary criterion of effectiveness) and the proportion of patients with improvement on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), the dynamics of visual-spatial orientation disorders (Benton test), sleep quality (Pittsburgh Sleep Quality Index scale) and the safety of therapy were evaluated., Results: Miladean demonstrated efficacy in the treatment of CDs: a statistically and clinically significant decrease in the overall score on the ADAS-Sod scale was shown (by 6.1 versus 4.7 and 3.5 points in the 2nd ( p =0.009) and 3rd ( p <0.05) groups) and an increase in the proportion of patients (96.9%) with clinically and statistically a significant improvement compared to the 2nd and 3rd groups ( p =0.019 and p <0.001 respectively). Miladean significantly improved the performance in the Benton test (1.20±1.66 vs. 0.64±1.69 points in group 3, p =0.026) and sleep quality (84.7% of patients with CDs), compared to placebo (63.9%) and memantine (64.3%) ( p =0.002 in both cases). Miladean was well tolerated, there were no cases of interaction with basic therapy drugs., Conclusion: The combination of many different pathogenetic effects of Miladean suggests that it has the ability to slow down the rate of progression of CDs and stabilize the condition of patients. The unique combination of active substances in Miladean has been proven to be effective and safe in the treatment of patients with CDs.

The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.

Long-term alcohol consumption causes the development of neuroinflammation in various brain structures. One of the mechanisms involved in this process is the increased activity of TLR-signaling intracellular pathways. Studies confirm the ability of ginseng extract or its individual ginsenosides to reduce the increased activity of TLR-signaling pathways. The aim of our study was to study the effect of the amount of ginsenosides obtained from the extract of the Panax japonicus cell line on the state of the TLR-signaling system in the nucleus accumbens and hippocampus of the rat brain in a model of long-term alcohol consumption during alcohol withdrawal. The results of the study showed that ginsenosides were able to make changes in the TLR signaling system, which has been altered by long-term alcohol consumption. A significant effect of ginsenosides on the level of TLR3 and TLR4 mRNA in the nucleus accumbens was found, while in the hippocampus, ginsenosides significantly affected the level of TLR7 mRNA. The effect of ginsenosides on the level of mRNA of transcription factors and cytokines involved in TLR-signaling was evaluated. Thus, results of our study confirm that ginsenosides are able to influence the state of TLR-signaling pathways, but this effect is multidirectional in relation to different brain structures. In the future, it seems interesting to evaluate the role of individual ginsenosides in relation to genes of TLR-signaling, as well as the effect of ginsenosides on other brain structures.

Nucleus accumbens (NAc) is the ventral part of the striatum of the brain; it is an important part of the mesolimbic pathway involved in the reward system that mediates the formation of various forms of addiction, in particular alcohol addiction. Neuroimaging data and in vitro studies indicate the development of a pronounced neurodegenerative process in the NAc, with long-term alcohol use, but the key mechanisms mediating this process remain unknown. In recent years, the attention of researchers has been focused on studying the system of Toll-like receptors (TLRs), the increased activity of which is clearly shown in the cerebral cortex and hippocampus during prolonged alcohol exposure, but there is a need to study the role of this system in other brain structures. In this study, we have shown that prolonged alcohol exposure (2 months) with moderate doses of ethanol (2 g/kg) promotes a pronounced increase in the expression of the Tlr4 gene and its endogenous ligand Hmgb1 in NAc during the period of alcohol withdrawal in rats. Injections of rifampicin (100 mg/kg) reduced the elevated expression level of Hmgb1, Tlr4, as well as pro-inflammatory cytokine genes (IL1β, IL6), while the administration of the drug increased the reduced level of mRNA of anti-inflammatory cytokines (IL10, IL11).