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.

Changes in Activity of Matrix Metalloproteinases and Serum Concentrations of Proinsulin and C-Peptide Depending on the Compensation Stage of Type 2 Diabetes Mellitus.

In patients with type 2 diabetes mellitus, serum activities of MMP-2 and MMP-7 were substantially decreased in comparison with apparently healthy individuals. At the decompensation stage, along with the increased content of glucose and glycated hemoglobin, a pronounced (3-fold) increase in proinsulin concentration was observed. On the contrary, MMP activity and C-peptide concentration decreased at this stage. The ratio of proinsulin concentration to MMP activity at the stages of diabetes mellitus compensation and subcompensation was approximately 1:50, while at the stage of decompensation it was 1:12. Thus, the ratio of these blood serum parameters can be used as an additional diagnostic marker of diabetes decompensation and severity of its complications.

Changes in Activity of Cysteine Cathepsins B and L in Brain Structures of Mice with Aggressive and Depressive-Like Behavior Formed under Conditions of Social Stress.

We studied activity of lysosomal cysteine proteases, cathepsins B and L, in brain structures (frontal cortex, caudate nucleus, hippocampus, and hypothalamus) of C57Bl/6J mice with aggressive and depressive-like behavior formed under conditions of chronic social stress (repeated experience of victories and defeats within 20 days). Mice with depressive-like behavior showed increased activity of cathepsin В in the hypothalamus and nucleus caudatus and increased activity of cathepsin L in the hippocampus compared to control animals not subjected to agonistic confrontations. In mice with aggressive behavior, protease activity in the studied brain structures was not changed. In 4 h after immune system activation with LPS (250 µg/kg), cathepsin L activity in the hippocampus of control mice increased in comparison with mice receiving saline. In contrast to control animals, LPS caused a decrease in activity of the enzyme in the caudate nucleus and frontal cortex of aggressive mice and in the hippocampus of mice with depressive-like behavior.

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.

Nonlinear Stimulated Raman Exact Passage by Resonance-Locked Inverse Engineering.

We derive an exact and robust stimulated Raman process for nonlinear quantum systems driven by pulsed external fields. The external fields are designed with closed-form expressions from the inverse engineering of a given efficient and stable dynamics. This technique allows one to induce a controlled population inversion which surpasses the usual nonlinear stimulated Raman adiabatic passage efficiency.

Cystatin C as a Marker of Progressing Cardiovascular Events during Coronary Heart Disease.

The role of cystatin C, an inhibitor of cysteine proteases, as an alternative and potent predictor of acute cardiovascular events in coronary heart disease (CHD) patients was examined and compared to that of other markers of cardiorenal abnormalities. The patients with CHD demonstrated elevated serum cystatin C, especially in cases with serious risk of cardiovascular complications. In comparison with other indicators of cardiorenal dysfunction, cystatin C can be viewed as an alternative predictor of cardiovascular complications, although its sensitivity is inferior to that of high-sensitivity C-reactive protein and natriuretic peptide.

[Proinsulin as a diagnostic biochemical marker of decompensated diabetes mellitus type II.]

The proinsulin is one of indices reflecting functional activity of pancreas. Under insulin-independent diabetes ration proinsulin/insulin increases. The study was carried out to evaluate content of proinsulin and other biochemical indices of blood serum depending on stage of compensation of diabetes mellitus type II. The content of proinsulin in blood serum was detected using "sandwich"-technique enzyme-linked immunosorbent assay (BioVender, Czechia). The concentration of proinsulin in blood serum of control group comprised 2,56 ± 0,23 nmol/l. No gender and age differences were established concerning content of proinsulin in blood serum of patients. The concentration of proinsulin was twice higher than control level in group of patients. Two main groups were singled out: one with high content (concentration thrice exceeded average value in control group) and another with low content of proinsulin (within standard value). The patients with stages of compensated and sub-compensated diabetes (n=35) retained low concentration of proinsulin. At the stage of decompensation of diabetes (n=40) concentration of proinsulin was thrice higher than standard value. This group was characterized by increasing of concentration of glucose, fructosamine and decreasing of concentration of C-peptide. At the stage of decompensation concentrations of triglycerides, total cholesterol and atherogenicity index increased reliably. The concentration of proinsulin at the stage of decompensation positively correlated with level of glucose and concentration of triglycerides. Therefore, measurement of concentration of proinsulin can be used as an important diagnostic criterion permitting to judge about degree of decompensation of diabetes and development of its complications.

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.

Comparative evaluation of opioid-induced changes in immune reactivity of CBA mice.

Comparison of IgM and IgG-humoral immune response of CBA mice immunized with SE (5 × 10(8) cells) to activation of µ- (DAGO, 100 µg/kg) and δ2- (DSLET, 100 µg/kg) opioid receptors was studied. Different effects of opioids on IgM and IgG antibody production and peripheral blood and spleen levels of CD4(+) and CD8(+) subpopulations were detected at the peak of immune response under these conditions.

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.

Involvement of dopamine D1 and D2 receptors in the rat nucleus accumbens in immunostimulation.

Analysis of the nature of changes in the immune response in operated Wistar rats showed that electrolytic lesioning of the nucleus accumbens, the site of the greatest density of dopamine D1 and D2 receptors, led to suppression of the immune response in animals immunized with sheep erythrocytes. Administration of SKF 38393 (20 mg/kg) and quinpirol (1 mg/kg), selective agonists of dopamine D1 and D2 receptors respectively, to sham-operated rats induced significant increases in immune responses. However, no immunostimulation was seen on administration of the selective dopamine D2 agonist quinpirol to animals with lesions to the nucleus accumbens as compared with controls. At the same time, treatment of animals with nucleus accumbens lesions using the dopamine D1 receptor agonist SKF 38393 had no effect on the immune response as compared with that in sham-operated animals given the D1 receptor agonist. These data provide evidence that dopamine D2 receptors in the nucleus accumbens have a role in the mechanisms of immunostimulation, though D2 receptors in other brain structures may also make some contribution to this process; D1 receptors in the nucleus accumbens make no significant contribution to controlling the immune response.

Immune response in Wistar rats with high and low level of situational anxiety.

A large sample of Wistar rats was divided into 2 groups of high-anxiety and low-anxiety animals by the time spent in the open arms of the elevated plus-maze. This selection was based on the criterion of time (low-anxiety animals, not less than 10 sec; high-anxiety animals, not more than 2 sec). Immunization with T-dependent antigen was performed on the day of behavioral testing. The number of rosette-forming cells in high-anxiety rats significantly decreased on day 5 after immunization. A genetically determined relationship probably exists between low activity of the immune response and high level of reactive anxiety.

Interaction between dopamine D1 and D2 receptors in modulation of the immune response.

The interaction between dopamine D1 and D2 receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D1 and D2 receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type.