Effect of Repetitive Transcranial Magnetic Stimulation on Serum Levels of Steroid Adrenal Hormones in Parkinson's Disease: Sex Differences.

In a parallel placebo-controlled study, we examined the effect of repetitive transcranial magnetic stimulation (rTMS) on serum concentrations of cortisol and dehydroepiandrosteron sulfate (DHEAS), and their relationships with clinical symptoms in men and women with Parkinson's disease. A 20-day course of real rTMS reduced the UPDRS and UPDRS III scores in patients with Parkinson's disease in comparison with the basal parameters (before rTMS), regardless of their sex. The level of cortisol did not change in men and women; at the same time, the content of DHEAS in men increased and before rTMS negatively correlated with the UPDRS scores. Sham rTMS had no effects on clinical parameters or hormonal levels. Possible mechanisms of sex-dependent differences in the effect of rTMS on the level of the neurosteroid hormone DHEAS are discussed.

Peculiarities of the Composition of Peripheral Immune Cells and Cytokine Profile in Brain Structures in Mutant DISC1-L100P Mice.

Intact Disc1-L100P mice carrying a point mutation DISC1Rgsc1390 in the second exon of the DISC1 gene (genetic model of schizophrenia) differ from the parental C57BL/6NCrl strain by higher content of CD3+ T cells and reduced number of CD19+B cells in the peripheral blood and spleen. Analysis of T cell subpopulations revealed an increase in the number of CD3+CD4+ T helpers in the blood of mutant mice and a decrease in the level of CD3+CD8+ suppressor/cytotoxic T cells and CD3+CD4+CD25+ T-regulatory cells. The distribution pattern of inflammatory (IL-1ß, IL-2, IL-6, IL-17, IFNγ, and TNFα) and anti-inflammatory (IL-4, IL-10) cytokines specific for Disc1-L100P mice was revealed in the brain structures involved in the pathogenesis of schizophrenia. A possible implication of immune mechanisms in the development of schizophrenia-like endophenotype of Disc1-L100P mice is discussed.

Content of Peripheral Blood T- and B-Cell Subpopulations in Transgenic A53T Mice of Different Age (A Model of Parkinson's Disease).

We analyzed the behavior and peripheral blood T- and B-cell subpopulations in mice overexpressing the mutant form of human α-synuclein (A53T) in comparison with mice of the wild type (WT) parent C57BL/6J strain. Behavioral phenotype and the content of various cell subpopulations of A53T mice depended on animal age. Young (2-month-old mice) were characterized by low emotionality and the most pronounced changes in cell subpopulation composition (an increase in CD3+T cells and CD4+T helper cells, a decrease in CD19+B cells along with unchanged content of CD3+CD4+CD25+T-regulatory cells and CD19+CD25+B-regulatory cells). In old A53T mice (10-month-old), movement impairments appeared and increased numbers of CD4+T helper cells and CD3+CD4+CD25+T-regulatory cells were revealed.

The composition of peripheral immunocompetent cell subpopulations and cytokine content in the brain structures of mutant Disc1-Q31L mice.

The DISC1 (disrupted in sсhizophrenia 1) gene is associated with brain dysfunctions, which are involved in a variety of mental disorders, such as schizophrenia, depression and bipolar disorder. This is the first study to examine the immune parameters in Disc1-Q31L mice with a point mutation in the second exon of the DISC1 gene compared to mice of the C57BL/6NCrl strain (WT, wild type). A flow cytometry assay has shown that intact Disc1- Q31L mice differ from the WT strain by an increase in the percentage of CD3+ T cells, CD3+CD4+ Т helper cells and CD3+CD4+CD25+ T regulatory cells and a decrease in CD3+CD8+ T cytotoxic/suppressor cells in the peripheral blood. A multiplex analysis revealed differences in the content of cytokines in the brain structures of Disc1-Q31L mice compared to WT mice. The content of pro-inflammatory cytokines was increased in the frontal cortex (IL-6, IL- 17 and IFNγ) and striatum (IFNγ), and decreased in the hippocampus and hypothalamus. At the same time, the levels of IL-1ß were decreased in all structures being examined. In addition, the content of anti-inflammatory cytokines IL-4 was increased in the frontal cortex, while IL-10 amount was decreased in the hippocampus. Immune response to sheep red blood cells analyzed by the number of antibody-forming cells in the spleen was higher in Disc1-Q31L mice at the peak of the reaction than in WT mice. Thus, Disc1-Q31L mice are characterized by changes in the pattern of cytokines in the brain structures, an amplification of the peripheral T-cell link with an increase in the content of the subpopulations of CD3+CD4+ T helpers and CD3+CD4+CD25+ T regulatory cells, as well as elevated immune reactivity to antigen in the spleen.

Cytokine Content in the Hypothalamus and Hippocampus of C57Bl/6J Mice with Depressive-Like Behavior.

The content of pro- and anti-inflammatory cytokines in the hypothalamus, hippocampus, and blood serum of C57Bl/6J mice with depressive-like behavior induced by 20-day social stress was analyzed in 4 h after immune stimulation with LPS (250 µg/kg). These animals are characterized by a tendency to an increase in the blood content of IL-6 and a decrease in the level of IL-10. Changes in cytokine content in the brain of mice with depressive-like state developed under these conditions were observed only in the hippocampus: the levels of IL-1ß, IL-6, TNFα, and IL-10 increased and the content of IFNγ decreased in comparison the corresponding parameters in the controls (not exposed to social stress) and aggressive animals. No changes in the levels of IL-2, IL-4, and IL-17 were revealed in the hypothalamus and hippocampus.

Therapeutic Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Neuroinflammation and Neuroplasticity in Patients with Parkinson's Disease: a Placebo-Controlled Study.

The parallel placebo-controlled study examined the therapeutic effects of dual-target repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (bilaterally) and the left prefrontal cortex (dorsolaterally) on spontaneous and mitogen-stimulating synthesis of pro- and anti-inflammatory cytokines by the blood cells and the level of brain-derived neurotrophic factor (BDNF) in blood serum of patients with Parkinson's disease. The significantly steeper positive clinical dynamics (assessed by UPRSD scale) observed in rTMS group in comparison with the placebo group was accompanied by a significant drop in spontaneous production of proinflammatory cytokines IFNγ and IL-17A. rTMS produced no significant effect on serum BDNF. The possible mechanisms of rTMS therapeutic action on the level of cytokines associated with neuroinflammation in patients with Parkinson's disease are discussed.

Cytokine Production by Splenic Cells in C57BL/6J Mice with Depression-Like Behavior Depends on the Duration of Social Stress.

We studied the influence of depression-like behavior developed in C57BL/6J mice under conditions of social stress of different duration on cytokine production by splenic cells. Imbalance of the pro- and anti-inflammatory cytokines was detected at the early stage of depression-like behavior (10-day experience of defeats): increased production of proinflammatory IL-2 and IL-6 cytokines along with a decrease in anti-inflammatory IL-10 level; the levels of IL-1ß, TNFα, IFNγ, and IL-4 remained unaffected. At later terms (20 days of confrontations), we revealed more pronounced changes in spontaneous production of proinflammatory cytokines that were not detected after shorter social stress. These findings suggest that cytokine profile depends on duration of social stress. Possible mechanisms of cytokine production during formation of depression-like state are discussed.

Effect of Antidepressants on Immunological Reactivity in ASC Mice with Genetically Determined Depression-Like State.

The effect of chronic treatment with antidepressant drugs fluoxetine (20 mg/kg) and imipramine (25 mg/kg) on the number of antibody-producing cells and the main T cell subpopulations in ASC mice characterized by genetic predisposition to depression-like states was studied at the peak of the SE-induced immune response (5×10(8)). Fluoxetine produced an immunostimulatory effect manifested in an increase in the relative and absolute number of IgM antibody-producing cells in the spleen and index of immunoreactivity (CD4/CD8). Administration of fl uoxetine to parental mouse strains without depression (CBA and AKR) had no effect (CBA) or reduced the immune response. The CD4/CD8 ratio did not increase under these conditions. Imipramine was ineffective in the correction of immune reactions in a depression-like state.

Changes in Production of Cytokines by C57Bl/6J Mouse Spleen during Aggression Provoked by Social Stress.

The effect of aggressive behavior shaped under social stress of various durations on the production of proinflammatory cytokines by splenic cells was examined on C57BL/6J mice. Aggressive mice were characterized by enhanced production of IL-2 and IFN-γ (released by T helper type 1 cells) and reduced secretion of TNF-α, whose major producers are monocytes and macrophages. Elevation of IL-2 and IFN-γ in aggressive mice resulted from enhancement of spontaneous and Con A-stimulated production, the most pronounced effect was demonstrated by the with a longer period (20 days) of victories. In contrast, spontaneous production of TNF-α was similar in control and aggressive mice, although LPS-stimulated production of this cytokine decreased after 10- and 20-day stress. The possible mechanisms of the changes in cytokine production are discussed.

[Effect of dopamine D1 and D2 receptor blockade on the immunostimulating effect of δ1 opioid receptor agonist DPDPE in mice with different psychoemotional states].

It is established that activation of delta1 opioid receptors with their selective agonist DPDPE(100 µg/kg) significantly increases IgM immune response not only in C57BL/6J mice with unchanged psychoemotional state, but also in mice displaying aggressive or depressive-like behavior in the social stress model (10 days of agonistic confrontations). SCH-23390 (1.0 mg/kg), selective antagonist of dopamine D1 receptors, and selective D2 receptor blocker haloperidol (1 mg/kg) prevented the immunostimulating effect of DPDPE in animals not subjected to social stress. At the same time, both SCH-23390 and haloperidol did not affect DPDPE-induced immunostimulation in mice engaged in aggressive or depressive-like behaviors.

[Effect of antipsychotic amisulpride on immune reactivity].

The effect of atypical antipsychotic solian (amisulpride), binding predominantly to dopamine D2/D3-receptors, on the immune reactivity has been studied in mice of the CBA strain with different psychoemotional states (aggressive and submissive behavior). In addition, the effect of solian on the expression of various CD-markers of lymphocytes in has been analyzed in vitro for patients with schizophrenia diagnosis. Chronic (10 days) administration of solian in mice at a dose of 5.0 mg/kg resulted in a significant suppression of the immune response to T-dependent antigen (sheep red blood cells). This effect was manifested in animals with both psychoemotional states, but was more expressed in aggressive animals. In the in vitro system, solian produced opposite effects on the expression of surface CD receptors in lymphocytes of patients with schizophrenia. It is suggested that solian does not only affects immune function through D2 receptors of the brain, but also directly influences immunocompetent cells.

[Effect of activation of serotonin 5-HT1A-receptors on the immune response in mice of the ASC strain with depressive-like behavior].

Selective activation of serotonin 5-HT(1A)-receptors produced different effects on immunological reactivity in mice of ASC strain with genetic predisposition to depressive-like behavior, and parental CBA and AKR strains displaying no depressive reactions. Administration of 5-HT(1A)-receptors agonist 8-OH-DPAT at low dose (0.1 mg/kg) affecting upon presynaptic receptors resulted in immunostimulation in CBA mice and did not change the immune response level in mice of ASC strain. Activation of postsynaptic 5-HT(1A)-receptors with higher dose of 8-OH-DPAT (1.0 mg/kg) caused immunosuppression in CBA and AKR strains while under the same conditions the immune response of ASC mice was increased. Decrease the immune reactions in ASC mice was observed only after application of 8-OHDPAT at dose of 5 mg/kg. The changes of functional activity of pre- and postsynaptic 5-HT(1A)-receptors under a high predisposition to depressive-like behavior providing different effects of this receptor activation on immune function are discussed.

[T-lymphocyte subpopulations and immune response in mice of the ASC strain with depressive-like behaviour].

Analysis of the content of CD16/32+, CD4+ and CD8+ -cells was perfomed in the peripheral blood and spleen ofmice of the ASC strain with high predisposition to depressive-like state in comparison with mice of parent CBA strain having no depressive behaviour. In both cases, ASC mice showed a decrease in the percentage of CD16/32+ and CD4+-cells along with an increase CD8 cells and lowering of immunoreactivity index (CD4+/CD8+). Changes in cellular subpopulations found in intact ASC mice was accompanied with animals' low capacity to respond to T-dependent antigen: sheep red blood cells at the dose of 5 x 10(8). In contrast to CBA mice the percentage and absolute number of IgM-antibody-forming cells were significantly decreased in the spleen of ASC mice on the 4th and 5th days after immunization as well as the numbers of IgG-antibody-forming cells on the 6th day of the immune response. Possible mechanisms underlying the immune reactivity inhibition under depressive-like state are discussed.

[Clinical and experimental research of immunomodulatory effect of amisulpride].

Study of immunomodulatory effect of atypical antipsychotic amisulpride has revealed a positive clinical effect after 6-week therapy of schizophrenic patients regarding both positive and negative symptoms. A decrease in activity of humoral immunity factors (B lymphocytes, immunoglobulins, HLADR(+)-cells) identified among schizophrenic patients in the process of amisulpride therapy can be attributed to a positive effect optimizing the ratio Th1/Th2. Amisulpride when used under experimental conditions produced a suppression of IgM-immune response in mice of the C57BL/6J strain. This effect was more expressed in animals with aggressive behavior pattern.

Immune response during activation of pre- and postsynaptic serotonin 5-HT(1A) receptors in C57Bl/6J mice at various stages of a depression-like state.

The development of a depression-like state in C57Bl/6J mice with repeated defeat experience (10 and 20 days) was accompanied by inhibition of the immune response (evaluated from the number of IgM antibody-producing cells). Activation of postsynaptic 5-HT(1A) receptors with a selective agonist 8-OH-DPAT (1.0 mg/kg) in these animals had no effect on the immune reaction. In mice without the experience of confrontations, stimulation of postsynaptic receptors caused a decrease in the number of IgM antibody-producing cells at the peak of the immune response induced by sheep erythrocytes (5×10(8) cells). However, the count of these cells remained unchanged in mice with a depression-like state (irrespective of the stage of disorder). Activation of presynaptic 5-HT(1A) receptors with 8-OH-DPAT (0.1 mg/kg) in control animals and mice with 10-day defeat experience was followed by immune stimulation. These changes were not observed in mice with a depression-like state caused by 20-day social stress.

Effects of chronic fluoxetine treatment on catalepsy and the immune response in mice with a genetic predisposition to freezing reactions: the roles of types 1A and 2A serotonin receptors and the tph2 and SERT genes.

ASC (Antidepressant-Sensitive Catalepsy) mice, bred for a high predisposition to catalepsy, are characterized by depression-like behavior and decreased immune responses. Chronic administration of fluoxetine, which is a selective serotonin reuptake inhibitor antidepressant widely used in clinical practice, to mice of this strain weakened catalepsy and normalized the number of rosette-forming cells in the spleen. In mice of the parental cataleptic strain CBA/Lac, fluoxetine had no effect on the level of catalepsy or the immune response. Analysis of the effects of fluoxetine on the functional activity of 5-HT(1A) and 5-HT(2A) receptors, and the expression of 5-HT(1A) receptor genes in the frontal cortex and midbrain and 5-HT(2A) receptors in the frontal cortex, as well as the tryptophan hydroxylase-2 and the serotonin transporter genes in the midbrain showed that the antidepressant had no effect on these parameters in ASC mice, but decreased the functional activity of 5-HT(2A) receptors in CBA/Lac mice. The possibility that the actions of fluoxetine on catalepsy and the immune response in mice with depression-like states are mediated via other serotoninergic mechanisms is discussed.

Involvement of presynaptic 5-HT(1A) receptors in immunomodulation in conditions of psychoemotional tension.

The development of an immune reaction in CBA mice during activation and blockade of serotonin 1A (5-HT(1A)) autoreceptors with highly selective agents has characteristic features depending on the behavioral stereotype formed. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg 15 min before immunization) did not alter the number of IgM antibody-forming cells in the spleen at the peak of the immune reaction (day 4) in aggressive mice, but increased the number in submissive mice, in which the immune response without treatment was lower than that in aggressive animals. Blockade of the same receptor type with WAY-100635 (0.1 mg/kg 30 min before immunization) led to a decrease in the immune response in animals with aggressive behavior and an increase in submissive animals. The question of the influences of agents acting on presynaptic 5-HT(1A) somatodendritic autoreceptors on the immune response, depending on the functional state of 5-HT(1A) receptors and the balance of activities in the serotoninergic and dopaminergic systems as a whole, is discussed.

Effects of 5-HT2A receptor stimulation and blocking on immune response.

Experiments on CBA mice showed that selective stimulation of 2A serotonin receptors with DOI agonist (1 mg/kg) led to suppression of the immune response and reduction of the spleen and peripheral blood CD8(+)T cell counts with the cytotoxic/suppressor function. Selective blockade of these receptors with ketanserin (1 mg/kg) had an opposite effect: immunostimulation with an increase in CD8(+)T cell count in the spleen. These data indicate the involvement of 2A serotonin receptors in immunosuppressive mechanisms of serotoninergic system.

[Immune response under activation of pre- and postsynaptic serotonin 5-HT1A-receptors in mice with depressive-like behavior].

Development of depressive-like state in mice of the C57BL/6J strain is accompanied by a considerable decrease in the immune response. A selective activation of presynaptic 5-HT1A-receptors (8-OH-DPAT, 0.1 mg/kg, for 15 min before immunization) markedly increased the immune response tested with the number of IgM-antibody-forming cells, and stimulation of postsynaptic 5-HT1A-receptors (8-OH-DPAT, 1.0 mg/kg, for 30 min before immunization twice) produced an immune suppression in control animals (mice without experience of victories and defeats). On the other hand, there were no changes in the immune response level following 8-OH-DPAT administration (0.1 and 1.0 mg/kg) in mice with depressive-like state. The role of pre- and postsynaptic 5-HT1A-receptors in immunomidulation in mice with depressive-like behaviour is discussed.

[Role of serotonin receptors in the delta-opioid immunosuppression].

The present study indicates involvement of serotoninergic (5-HTergic) mechanisms in immunosuppression by DSLET (100 mkg/kg), a selective agonist of the delta2-opioid receptors, in CBA mice. 8-OH-DPAT (0.1 mg/kg), a selective agonist of the 5-HT(1A)-autoreceptors, WAY-100635 (1, 3 mg/kg) and ketanserin (1, 3 mg/kg), a selective antagonists of the postsynaptic 5-HT(1A)- and 5-HT(2A)-receptors, respectively, prevented immunosuppressive effect of DSLET. A possible differential role for 5-HT-receptors in delta-opioid immunosuppression is suggested.