[The influence of fluoxetine on neuroimmune interaction in multiple sclerosis]. / Vliyanie fluoksetina na neiroimmunnoe vzaimodeistvie pri rasseyannom skleroze.

OBJECTIVE: To study the effect of fluoxetine on Th17- and Th1-immune response, which plays an important role in the pathogenesis of multiple sclerosis (MS). MATERIAL AND METHODS: Ten patients with relapsing-remitting MS and ten healthy subjects were examined. The functions of Th17- and Th1-immune responses were assessed by the production of cytokines interleukin-17 (IL-17) and interferon-gamma (IFN-γ) by CD4+ T cells stimulated with macrophages or microbeads coated with anti-CD3 and anti-CD28-antibodies. To assess the effect of fluoxetine on the macrophages-induced Th17- and Th1-immune response, macrophages were pre-incubated in the presence of fluoxetine and co-cultured with autologous CD4+ T-cells. In the case of stimulation of CD4+ T-cells with anti-CD3/CD28-microbeads, fluoxetine was added directly to the T-helper cells before adding of microbeads. In addition, we evaluated the effect of fluoxetine on the production of the factors of differentiation of Th17-cells cytokines IL-6 and IL-1ß by macrophages. The levels of cytokines in the cell culture supernatants were measured by ELISA. RESULTS: The production of IL-17 and IFN-γ by CD4+ T-cells stimulated with macrophages or anti-CD3/CD28-microbeads was comparable between the groups. Fluoxetine suppressed the production of IL-17 and IFN-γ by anti-CD/CD28-stimulated CD4+ T-cells in both groups. Fluoxetine also suppressed the production of IL-6 and IL-1ß by macrophages as well as their ability to induce IL-17 and IFN-γ production by CD4+ T-cells in both groups. CONCLUSIONS: Fluoxetine may have an anti-inflammatory effect in MS that could be mediated by suppression of Th17- and Th1-cells or macrophage-induced Th17- and Th1-immune response.

[Prospects for the use of polyphenols in multiple sclerosis]. / Perspektivy primeneniya polifenolov pri rasseyannom skleroze.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease. Therapy for MS does not always slow down the progression of the disease. In many cases, pathogenetic therapy of MS leads to serious side-effects, in particular, to immunosuppression, limiting using of various disease modifying therapy (DMT) in MS. In this regard, it is important to study the potential use of drugs that have immunomodulatory and neuroprotective effects, as well as a favorable safety profile. Polyphenols (compounds containing phenolic and hydroxyl groups, often of natural origin) have the ability to modulate immunoregulatory targets, reducing the production of various pro-inflammatory cytokines that play an important role in the pathogenesis of MS. The combined use of DMT and substances with a favorable safety profile, anti-inflammatory activity, and the ability to penetrate the blood-brain barrier, such as polyphenols, may be one of the promising strategies in the treatment of MS to improve the quality of life of patients. In this review, we consider the mechanisms of action of polyphenols in MS, their application in experimental models of MS, and the results of clinical studies of polyphenols in MS.

[The role of macrophages in the development of neuroinflammation in multiple sclerosis]. / Rol' makrofagov v razvitii neirovospaleniya pri rasseyannom skleroze.

Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative disease of the central nervous system with an autoimmune mechanism of development. It is known that along with T- and B-lymphocytes, cells of the innate immune system also play a significant role in the pathogenesis of MS. Macrophages are central to the functioning of the innate immune response and, depending on the phenotype, have pro-and anti-inflammatory properties. In the central nervous system, resident macrophages form microglia capable of presenting antigens and producing cytokines and, depending on phenotype, may participate in the development of autoimmune inflammation or maintaining immunological tolerance. The brief report presents data on the participation of macrophages in the pathogenesis of experimental autoimmune encephalomyelitis and MS. In addition, current methods of modulation of macrophage functions for the treatment of MS are discussed.

[Blockade of D1-like dopaminergic receptors suppresses Th17-cell function in multiple sclerosis]. / Blokada D1-dofaminovykh retseptorov podavlyaet funktsii Th17-kletok pri rasseyannom skleroze.

OBJECTIVE: To investigate the direct effect of D1-like dopaminergic receptors antagonist on Th17-cells function in multiple sclerosis (MS) in vitro. MATERIAL AND METHODS: Forty-one relapsing-remitting MS patients and twenty-five healthy subjects were examined. The functional activity of Th17-cells was assessed by the ability to produce IL-17 and IFN-γ by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells, stimulated with microbeads coated with anti-CD3/anti-CD28-antibodies. To study the involvement of D1-like dopaminergic receptors in modulation of Th17-cell function, the samples of PBMCs or CD4+ T-cells were cultured in the presence of dopamine and/or specific D1-like dopaminergic receptors antagonist (SCH23390). Cytokine levels in cell culture supernatants were measured by ELISA. RESULTS: The production of IL-17 and IFN-γ by stimulated PBMCs were higher in MS patients during relapse than in MS patients during clinical remission or in healthy subjects. The production of cytokines by stimulated PBMCs or CD4+ T-cells in MS patients during clinical remission and healthy subjects was comparable. Dopamine reduced the production of cytokines by PBMCs and CD4+ T-cells in all groups. Blockade of D1-like dopaminergic receptors did not affect the dopamine-mediated cytokine suppression in MS patients and healthy subjects. Blockade of D1-like dopaminergic receptors directly suppressed cytokine production by PBMCs and CD4+ T-cells in MS patients and healthy subjects. CONCLUSIONS: Dopamine and blockade of D1-like dopaminergic receptors have an inhibitory effect on Th17-cell function in MS. The activation of D2-like dopaminergic receptors could mediate the inhibitory effect of dopamine on Th17-cells.

[The prospect of dopaminergic therapy in multiple sclerosis]. / Perspektivy dofaminergicheskoi terapii pri rasseyannom skleroze.

Dopamine is a direct mediator of neuroimmune interactions. Recent studies show that by acting on the dopaminergic receptors, it is possible to modulate Th17-immune response, which play a crucial role in the pathogenesis of multiple sclerosis. Dopamine can modulate Th17 cells function as well as dendritic cell-mediated Th17-immune response that allows considering dopaminergic receptors as a new therapeutic target in multiple sclerosis. In this short communication, the prospects of using dopaminergic therapy as a pathogenetic treatment for multiple sclerosis are discussed.

[Ultrastructural changes in the endocardium and endocrine cardiomyocytes in the wall of the left atrial appendage in patients with atrial fibrillation]. / Ul'trastrukturnye izmeneniya endokarda i endokrinnykh kardiomiotsitov v stenke levogo ushka bol'nykh s fibrillyatsiei predserdii.

OBJECTIVE: To study ultrastructural changes in endocardial tissues and endocrine cardiomyocytes of the left atrial appendage in patients with atrial fibrillation. MATERIAL AND METHODS: Electron microscopy was used to examine the endocardium and endocrine cardiomyocytes of the left atrial appendage in 8 patients with long-standing paroxysmal and persistent atrial fibrillation and in one patient with coronary heart disease without rhythm disturbance (a control group). RESULTS: The investigation revealed that all the patients with atrial fibrillation had similar ultrastructural changes in all endocardial layers and endocrine cardiomyocytes of the left atrial appendage. The endothelium showed massive desquamation of endothelial cells. Predominantly single sharply flattened cells and small cytoplasmic fragments remained on the endocardial surface. The latter devoid of endothelial coating was represented by subendothelial loose connective tissue with noticeable signs of edema. The latter was also observed in the dense fibrous connective tissue of the endocardium. The accumulation of large amounts of edema fluid in the subendothelium led to endothelial cell flattening and desquamation. There was no leukocytic infiltration in the tissue of the endocardium or fibrin and desquamated endothelial cell accumulation on its surface. The endocrine cardiomyocytes exhibited disorders as cytoplasmic swelling, complete or partial lysis (necrosis) of individual myofibrils, and lower levels of endocrine granules and their location near or in direct contact with the sarcolemma. CONCLUSION: The study has shown that long-standing atrial fibrillation deteriorates the main factors that determine normal endothelial function: edema in subendothelial tissue disrupts its interaction with endothelial cells and leads the latter to detach from the endocardium; ultrastructural changes in the endocrine cardiomyocytes that produce hormones can impair systemic blood pressure control and intracardiac hemodynamics.

[The role of mitochondria in pathological mechanisms of innate immunity in multiple]. / Rol' mitokhondrii v realizatsii patologicheskikh mekhanizmov vrozhdennogo immuniteta pri rasseyannom skleroze.

The review discusses the role of mitochondria in multiple sclerosis (MS). Previously, damage to the mitochondria was regarded as a manifestation of secondary damage to axons and neurons, i.e. as a marker of neurodenegation. Recently, the role of mitochondria in the early stages of MS development, when they could participate in the activation of innate immunity and trigger activation of autoimmune responses of acquired immunity, has been increasingly discussed. The role of polymorphism mitochondrial DNA changes in MS is discussed.

[The influence of fluoxetine on interleukin-6 and interleukin-1ß production by dendritic cells in multiple sclerosis in vitro]. / Vliyanie fluoksetina na produktsiyu dendritnymi kletkami interleikina-6 i interleikina-1ß pri rasseyannom skleroze in vitro.

THE AIM OF THE STUDY: Was to evaluate the effect of selective serotonin reuptake inhibitor fluoxetine on the production of cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) by dendritic cells in multiple sclerosis (MS). MATERIAL AND METHODS: 5 patients with relapsing-remitting MS and five healthy subjects were examined. Levels of IL-6 and IL-1ß were measured by ELISA in culture supernatants obtained from lipopolysaccharide stimulated dendritic cells. To assess the effect of fluoxetine on cytokine production, dendritic cells were stimulated in the presence of fluoxetine and antagonists of 5-HT1A-, 5-HT2A-, 5-HT2B-receptors or agonist of 5-HT2B-receptors. RESULTS: Cytokine production by dendritic cells was comparable in both groups. Fluoxetine suppressed IL-6 and IL-1ß production in both groups. Blockade of 5-HT2B-receptors with specific antagonist RS 127445 reduced the inhibitory effect of fluoxetine on IL-1ß production in both groups and IL-6 production in healthy subjects. In contrast, activation of 5-HT2B-receptors by specific agonist BW 723C86 increased the inhibitory effect of fluoxetine on IL-6 production by dendritic cells in both groups, but did not affect on IL-1ß production. CONCLUSION: These data suggest an anti-inflammatory effect of fluoxetine in MS by modulating pro-inflammatory cytokines production by dendritic cells. This effect could be mediate by activation of 5-HT2B-receptors.

[New directions of immunocorrection in multiple sclerosis]. / Novye napravleniia immunokorrektsii pri rasseiannom skleroze.

Multiple sclerosis is a central nervous system disease with autoimmune and neurodegenerative mechanisms of development. This disease can lead to severe disability and neurological defects. Although its etiology and pathogenesis remain unclear, research data show that multiple sclerosis is a multifactorial disease, the development of which depends on environmental factors, as well as a genetic predisposition. The impact of these factors lead to the death of neural cells, accompanied by demyelination of nerves and neuronal dysfunction. Therapy of multiple sclerosis is based on the use of anti-inflammatory and immunomodulating substances, however, there are certain disadvantages associated with the constant use of these drugs and a possible change in dosage over time. This review discusses the pathogenesis of multiple sclerosis and the role of various subpopulations of immune cells in the development of diseases, as well as existing approaches to therapy. It is noted that immunoreconstitution therapy has advantages over immunomodulation and immunosuppression maintenance therapy for some patients. Thus, short courses of therapy provide more adequate treatment for patients and lower risks of adverse events associated with chronic immunosuppression. The review also discusses the data of clinical studies on the immunoreconstitution therapy drugs, such as alemtuzumab, ocrelizumab and cladribine. It is noted that nowadays the exact mechanisms underlying this type of therapy remain unclear. In this regard, further studies are needed to explain the therapeutic effects. It is assumed that patients with a high risk of multiple sclerosis progression are the optimal group of patients for the early use of selective immunoreconstitution therapy. Thus, immunoreconstitution therapy may be the treatment of choice for many patients with highle active multiple sclerosis.

[The pegylated form of interferon beta in the treatment of multiple sclerosis]. / Pegilirovannaia forma interferona beta v terapii rasseiannogo skleroza.

Interferons-beta (IFN-ß) along with glatiramer acetate is one of the most commonly used disease modifying treatment (DMT) of multiple sclerosis (MS) associated with effectiveness and acceptable safety profile. At the same time, therapy with IFN-ß has a number of limitations associated with a high frequency of injections and production of neutralizing antibodies. The development of the pegylated form of IFN-ß (PEG-IFN-ß) is aimed at resolving these issues. This article reviewed the mechanism of action, efficacy, safety and tolerability of PEG-IFN-ß in the treatment of MS.

[Serotonergic system as a therapeutic target in multiple sclerosis]. / Serotoninergicheskaia sistema kak terapevticheskaia mishen' pri rasseiannom skleroze.

The article presents the current literature on the role of serotonin in immunomodulation in multiple sclerosis, in particular, on the effect of serotonin on Th17-immune response and function of dendritic cells. The role of serotonin in the regulation of the gut-brain axis and the prospects for serotoninergic drugs as pathogenetic therapy in multiple sclerosis are discussed.

[Norepinephrine and intestinal microbiome in the early stages of demyelination: clinical-immunological parallels]. / Noradrenalin i mikrobiom kishechnika na rannikh stadiiakh demieliniziruiushchego protsessa: kliniko-immunologicheskie paralleli.

Biogenic amines are key mediators of neuroimmune interaction and may influence on multiple sclerosis (MS) pathogenesis and MS course. At the same time, the role of biogenic amines in immunoregulation of early stages of demyelination, in particular clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) is still unclear. This literature review addresses a role of norepinephrine in the regulation of neuroimmune interactions in the early stages of the demyelination. Neuropsychological disorders, immunological characteristics, gut-brain axis as well as the role of norepinephrine in these interactions in patients with CIS, RIS and early MS are discussed.

[Changes in the quality of life in patients with multiple sclerosis treated with ocrelizumab]. / Izmeneniia kachestva zhizni patsientov s rasseiannym sklerozom na fone kursa lecheniia okrelizumabom.

AIM: To study the quality of life (QoL) in patients with multiple sclerosis (MS) treated with ocrelizumab for at least 12 months. MATERIAL AND METHODS: Thirty-eight patients were observed, including 13 with primary progressive MS (PPMS), 15 with highly active relapsing-remitting MS (HAMS) and 10 with secondary progressive MS (SPMS) with relapses. QoL was studied using unspecific SF-36 and MS-specific MusiQoL questionnaires. Depression and fatigue were assessed with the Beck Depression Scale (BDS) and the Modified Fatigue Impact Scale (MFIS). RESULTS AND CONCLUSION: Basic characteristics of QoL indexes of the patients were similar to those previously reported for these MS variants. After 6 and 12 months, a significant increase in the indexes of the majority of SF-36 and MusiQoL scales was identified that shows a significant improvement in both physical and psychological domains of QoL. The significant and rapid decrease in depression severity after 6-month treatment with ocrelizumab may at least in part be associated with improvement of indexes of vitality, general health, social relations and the total QoL score.

[Dendritic cells in multiple sclerosis]. / Dendritnye kletki pri rasseiannom skleroze.

Main functions, structure and stages of development of dendritic cells (DCs) are reviewed. A role of DCs in the development of immune tolerance and autoimmune diseases as well as involvement of DCs in the immunopathogenesis of multiple sclerosis (MS and their therapeutic potential in the treatment of MS are discussed.

[Gut human microbiota and multiple sclerosis]. / Kishechnaia mikrobiota cheloveka i rasseiannyi skleroz.

Recently the relationship between gut microbiota changes and the development of immune-mediated diseases of the central nervous system (CNS) has been reported. This review presents literature data on the effect of gut microbiota on the function of the immune and nervous systems. The authors discuss possible mechanisms of the relationship between gut microbiota changes and CNS diseases on the model of multiple sclerosis (MS).

[Pathomorphological characteristics and risk factors of asymptomatic cerebral infarction based on the results of a cross-sectional hospital-based study]. / Patomorfologicheskie osobennosti i faktory riska asimptomnogo infarkta golovnogo mozga po dannym sektsionnogo gospital'nogo issledovaniya.

AIM: To study the prevalence, pathomorphological characteristics and risk factors of asymptomatic cerebral infarction (CI) based on the results of post-mortem studies and clinical charts of patients. MATERIAL AND METHODS: The autopsies of 735 patients died due to different diseases were analyzed using continuous sampling method. CI lesions were found in 86 patients (47 women, 39 men, mean age 76.3±10.5 years). Morphological parameters of CI and cardiovascular risk factors were analyzed. RESULTS AND CONCLUSION: There were mean 2.7±1.5 CI lesions per patient in the main group: 47 (54.6%) patients had ≥3 lesions, 9 (10.5%) - 2 lesions and 30 (34.9%) - 1 lesion. The significantly higher frequency of cardiovascular risk factors was found in CI patients (arterial hypertension, diabetes mellitus, atrial fibrillation, tobacco smoking) while the adherence to prevention strategies was lower compared to patients without CI.

[The influence of catecholamines on Th17-cells in multiple sclerosis]. / Vliyanie katekholaminov na Th17-kletki pri rasseyannom skleroze.

AIM: Тo investigate the possible association between clinical characteristics of multiple sclerosis (MS), quantitative and qualitative characteristics of Th17, dopamine and norepinephrine concentrations in the serum in patients with multiple sclerosis (MS). MATERIAL AND METHODS: A comprehensive neurological and immunological examination of 43 patients with relapsing-remitting-MS (RR-MS) was performed. All patients were subjected to a standard neurological examination with assessment of the EDSS score. Dopamine and norepinephrine concentrations in serum were measured by enzyme-linked immunosorbent assay (ELISA). Percentage of Th17-cells was determined by flow cytometry. The functional activity of Th17- and Th1-cells was assessed by the production of interleukin-17 (IL-17) and interferon-gamma (IFN-γ), respectively, by peripheral blood mononuclear cells (PBMC) stimulated with microbeads coated with anti-CD3 and anti-CD28-antibodies. RESULTS: The percent Th17-cells and cytokine production was significantly higher in MS patients with the exacerbation of disease than in the control group or remission, while the dopamine level was lower. Norepinephrine levels in MS patients in the acute stage and remission were comparable, but nevertheless, reliably lower than in the control group. CONCLUSION: The results suggest the inhibitory effect of catecholamines on Th17 cells.

[Psychoneuroimmunology and multiple sclerosis]. / Psikhoneiroimmunologiia i rasseiannyi skleroz.

In this review, the authors discuss interactions between mental, nervous and immune systems in multiple sclerosis, an impact of psycho-emotional stress on disease development and progression as well as possible mechanisms of these interactions.