[Dihydroquercetin as a systemic neuroprotector for the prevention and treatment of ß-amyloid-associated brain diseases]. / Digidrokvertsetin kak sistemnyi neiroprotektor dlya profilaktiki i lecheniya ß-amiloid-assotsiirovannykh zabolevanii golovnogo mozga.

Dihydroquercetin (DHQ) is a plant-derived polyphenol belonging to the group of flavonoids. In models associated with abnormal accumulation of ß-amyloid in the brain (Alzheimer's disease and cerebral amyloid angiopathy), DHQ demonstrates the ability to disaggregate toxic forms of ß-amyloid and prevent their formation. It is believed that this phenomenon underlies the protective effect of DHQ on brain neurons. However, pharmacokinetic data doubt the central mechanism of action of DHQ because this compound does not penetrate well into the brain. A hypothesis is put forward about the systemic nature of the neuroprotective action of DHQ, since this compound has multiple biological activities at the level of the whole organism. To characterize DHQ (and similar compounds), it is proposed to introduce the term «systemic neuroprotector¼.

[Anthocyanins for the prevention and treatment of neurodegenerative diseases]. / Antotsiany dlya profilaktiki i lecheniya neirodegenerativnykh zabolevanii.

Anthocyanins are water-soluble polyphenolic pigments widely present in fruits and vegetables. These compounds have extensive biological activity and are able to penetrate the brain and modulate its functions. In neurodegenerative processes, anthocyanins contribute to the survival of neurons. The mechanisms of the neuroprotective action of anthocyanins are associated with their antioxidant, anti-inflammatory, antitoxic, and anti-apoptotic activities. The ability of anthocyanins to act on multiple therapeutic targets at once makes them useful for the prevention and treatment of the initial stages of neurodegenerative diseases. Anthocyanins have low stability and bioavailability which creates problems for their therapeutic use. Methods for the stabilization and delivery of anthocyanins into the body are considered.

[Gut microbiome as a therapeutic target in the treatment of depression and anxiety]. / Kishechnyi mikrobiom kak terapevticheskaya mishen' pri lechenii depressii i trevogi.

There is a bi-directional connection between the gut microbiome and the brain. Changes in the composition of the microbiome affect emotions, behavior, and the stress response involved in the pathogenesis of depression. Depression and anxiety are often associated with dysbiosis and inflammatory bowel disease. Dysbiosis enhances stress response and low-grade systemic inflammation, and vice versa. This vicious circle may be responsible for the formation of depression. Antidepressants therapy should be accompanied by the elimination of dysbiosis. For these purposes diet, prebiotics, probiotics and faecal microbiota transplantation can be used. The advantages and disadvantages of each method are considered. The manipulation of microbiome composition has been shown to have great therapeutic potential in the treatment of depression and anxiety.

[Curcumin as an ajuvant treatment of depression: mechanisms of action and application prospects]. / Kurkumin kak vspomogatel'noe sredstvo lecheniia depressii: mekhanizmy deistviia i perspektivy primeneniia.

Curcumin, a natural compound found in the rhizomes of turmeric, has a pronounced anti-inflammatory activity. Rodent models of depression show that this activity is similar to the effect of antidepressants (AD). Experimental data indicate that this activity may be related to the effect of curcumin on the monoamine cycle, oxidative and nitrosative stress, neurogenesis, hypothalamic-pituitary-adrenal, and immune systems. A number of meta-analyzes indicate the effectiveness of the combined use of curcumin with antidepressants in the treatment of depression. The mechanism of action of curcumin, as well as the prospects for its further use are considered.

[Neurobiological effects of theanine and its possible use in neurology and psychiatry]. / Neirobiologicheskie éffekty teanina i ego vozmozhnoe ispol'zovanie v nevrologii i psikhiatrii.

Theanine is an analog of glutamate and the major aminoacid in green tea. It has received growing attention in recent years because of its beneficial effects on the central nervous system. Theanine was shown to increase levels of brain-derived neurotrophic factor and to stimulate neurogenesis. Anti-stress and calming effects of theanine are the most apparent and well-studied. A number of studies showed neuroprotective effects of theanine after an ischemic cerebral injury or the exposure to toxic chemicals. It also improved cognitive function including attention, memory and learning. Recent studies demonstrated a promising role of theanine in augmentation therapy for major depressive disorder and schizophrenia. Theoretical grounds for using theanine in treatment of bipolar disorder, anxiety disorder and some neurodegenerative disorders are discussed.

[Risk assessment of thrombotic events in patients with schizophrenia and schizoaffective disorder in the acute state: the 'fibrinodynamics' technology]. / Otsenka riska tromboticheskikh narushenii u bol'nykh shizofreniei i shizoaffektivnymi rasstroistvami v ostrom periode bolezni s ispol'zovaniem tekhnologii 'fibrinodinamika'.

AIM: To assess the risk of thrombotic events in patients with schizophrenia and schizoaffective disorder based on 'fibrinodynamics' technology. MATERIAL AND METHODS: A group of 76 women, including 38 with paranoid schizophrenia (F20.0), 18 with schizoaffective disorder (F25.1) in the acute stage, and 20 healthy controls, participated in the study. The technology includes the study of coagulation and fibrinolysis, Karmin author software, and calculation of peak time and hemostasis potential of spontaneous clots. Growth and lysis of fibrin clots were studied in plasma purified from platelets. All preanalytic procedures were conducted within 30 minutes after blood sampling. Blood serum was studied separately using the neuroimmunological test. Dynamic of brightness profiles of the clots was determined and a number of parameters (peak time and hemostasis potential of spontaneous clots) were calculated using the Karmin software. RESULTS: In patients with schizophrenia, the dynamic brightness profile of the clots has two peaks: the first peak is formed as a result of the growth and lysis of the clot initiated by the activator, the second peak is due to the growth and lysis of spontaneous clots in the volume of the measuring cuvette far from the activator. In healthy donors, the second peak under experimental conditions is absent. In the group of schizophrenic patients, a strong negative correlation is observed between the peak time of the second peak and the activity of leukocyte elastase (Spearman R = -0.75, p<0.0001), i.e. the greater the activity of elastase, the earlier the maximum of the second peak is formed and vice versa. In the control group, there is no such correlation. Evaluation of the potential of hemostasis of spontaneous clots showed that in 42% of schizophrenic patients this parameter is shifted above the norm, which indicates an increased risk of thrombosis of small brain arteries in these patients. CONCLUSION: The developed technology of 'fibrinodynamics' has a good potential for introduction into personalized medicine to identify increased risks of thrombosis of small cerebral vessels in patients with acute schizophrenia leading to the development of cognitive disorders and to control the normalization of hemostasis with antiplatelet or anticoagulant drugs.

[Platelet serotonergic parameters and clinical symptoms of psychosis in patients with episodic progressive schizophrenia].

A sample included 59 patients, 38 males and 21 females, mean age (M+/-SD) 33,4+/-10,2 years, age-at-onset 26+/-9,5 years, illness duration 7,8+/-6,1 years, with episodic progressive schizophrenia (ICD-10: schizophrenia, paranoid type, F20.0) with continuous course at the stage of exacerbation. Clinical symptoms were assessed using the PANSS. Platelet 5-HT content, 3H-serotonin uptake (Vmax), 3H-imipramine receptor density (Bmax), high- and low molecular weight human serotonin platelet transporter protein immunoreactivity (HMW-SERT and LMW-SERT values) were measured. The most frequent psychotic symptoms were delusions, conceptual disorganization and hallucinations, with the majority of patients experiencing from one to three symptoms. A significant increase of platelet 5-HT content and 3H-imipramine receptor density (Bmax) was found in male patients. In the male group, delusions, conceptual disorganization and hallucinations as well as PANSS psychotic cluster scores were correlated positively with 5-HT content and negatively with HMW-SERT and LMW-SERT values. Possible reasons of the differences in correlations of platelet 5-HT serotonin and serotonin transporter values with psychotic symptoms are discussed. The results are additional evidence for the involvement of serotonergic dysfunction in the pathogenesis of schizophrenic psychoses. They confirm the usefulness of testing of platelet 5-HT content and SERT immunoreactivity as biological markers of schizophrenic psychoses, in particular for male patents.

[Parameters of platelet serotonin system in patients with schizophrenia treated with olanzapine: a search for the serotonergic predictors of therapeutic efficacy].

Fifty-nine patients, 21 women and 38 men, with ICD-10 diagnosis of schizophrenia (F20.0), attack-like type, were treated with olanzapine during 28 weeks (8-weeks of acute and 20-weeks of maintenance therapy). Evaluation of clinical symptoms measured by the Positive and Negative Syndromes scale (PANSS) revealed that female patients responded better to therapy as compared to male ones, with PANSS total, PANSS negative and PANSS general psychopathological scores being significantly reduced (p < 0.006) in females after 1 week of the treatment and in males--after 2 weeks. In the female group, a reduction of PANSS total score by 50% in the acute stage of treatment qualified as a very good response was observed in 7 (33%) patients and in the male group--in 1 (2.7%). The between-groups difference was highly significant (p = 0.002). When examined for a rate of 3H-serotonin uptake into platelets, density of sites of 3H-imipramine binding on the whole platelets, platelet serotonin level and levels of high- also low-molecular weight forms of platelet immunoreactive serotonin transporter protein, a significant decrease of the platelet serotonin level, comparing to controls, was detected in the female group before treatment. During the treatment, this parameter gradually increased up to control level. Other parameters did not change significantly for 28-weeks of therapy and did not differ from the control values. There were positive correlations between the levels of platelet serotonin before treatment and subsequent reduction of the PANSS total and positive subscale scores in the female group. In responders with a very good treatment-related response, the serotonin level in the platelets before treatment was higher compared to the values in resistant patients: 5.4 +/- 2.5 and 2.7 +/- 1.3 nmol/10(9) cells, respectively. Relative risk (RR) of unfavorable treatment outcome in patients with initially reduced levels of platelet serotonin was approximately twice lower (RR = 1.83; Cl 95% 1.1-34.9) than that in patients with normal or elevated levels of platelet serotonin. The results suggest that selection of patients with initial higher level of platelet serotonin before olanzapine treatment can reduce the risk of non-responding to therapy by 36%.

[Levels and molecular heterogeneity of serotonin transporter protein in platelets of patients with different mental diseases: a comparative analysis with the use of monoclonal and polyclonal antibodies]. / Soderzhanie i molekuliarnaia geterogennost' belka--perenoschika serotonina v trombotsitakh bol'nykh s razlichnymi psikhicheskimi zabolevaniiami: sravnitel'nyi analiz s ispol'zovaniem monoklonal'nykh i poliklonal'nykh antitel.

Polyclonal (PAb) and monoclonal (MAb) antibodies to CT2-epitope of the C-terminal fragment of serotonin transporter (SERT) protein were used to study the levels and molecular heterogeneity of platelet SERT in healthy donors and patients with affective (AD) and somatoform (SD) disorders, schizoaffective disorder (SAD) and schizophrenia. SERT was found to exist as high molecular wight (HMW) and low molecular weight (LMW) forms separated after electrophoresis. The levels of HMW and LMW forms of SERT were significantly, decreased in mentally ill patients as compared to healthy individuals. Unlike PAb, horse radish peroxidase (HRP)-conjugated MAbs were more sensitive and specific to SERT and could detect the LMW form of SERT as a duplet protein form with MW about 40 and 43 kDa. The MAb to CT2 C-terminal fragment of SERT conjugated with HRP is considered to be a new valuable tool for further investigation of SERT expression, properties, and posttranslation modification in the controls and in patients with different psychopathology.

The state of the serotonin transporter protein in the platelets of patients with somatoform [correction of somatiform] disorders.

The role of the serotonin transporter protein (STP) in the development of somatoform [corrected] disorders was addressed in a correlational study of the levels of immunoreactive STP (IR-STP) using site-specific antibodies against the least conserved (among a group of other cotransporters) epitope at the C-terminal of STP and the level of anxiety symptoms in patients with somatoform [corrected] disorders. A total of 22 patients were studied, with DSM-IV diagnoses of somatoform [corrected] disorders, along with 32 mentally healthy subjects of comparable age and sex. Immunoblotting of IR-STP from patients from healthy donors produced a diffuse band between 68 and 105 kDal and a clear narrow band at 43 kDal. The 43-kDal IR-STP protein was almost completely absent from most patients, as compared with the levels of this protein in healthy donors. This result suggests an abnormality of STP processing or, perhaps, alternative splicing of the gene encoding STP in patients with somatoform [corrected] disorders, and this appears to reflect the dysfunction in serotoninergic transmission in the CNS in these patients.

[The status of serotonin protein -- a serotonin transporter in thrombocytes in patients with somatoform disorders]. / Sostoiane belka -- perenoschika serotonina v trombotsitakh u bol'nykh s somatoformnymi zabolevaniiami.

The role of serotonin transporter (SERT) protein in the development of somatoform disorders (SD) was investigated. An association study was performed in terms of the evaluation of the level of SERT immunoreactive (IR-SERT) protein using site-specific antibodies directed at SERT C-terminus fragment, poorly conserved among the other cotransporters. The level of the anxious symptomatology was also estimated in the patients with SD. 22 patients, who met DSM-IV criteria for somatoform disorders, and 32 normals were examined. In platelets from normals, IR-SERT protein migrated as a difuse band between 68 and 105 kDa, and a major sharper band at 43 kDa. Almost complete disappearance of platelet 43 kDa IR-SERT protein band was observed in most of the patients with SD. These findings permitted to suggest a possibility of either biosynthetic or processing abnormality of SERTs in the affected population, that might reflect a dysfunction of serotonin neurotransmission in CNS of the patients with SD.

[Function of the serotoninergic system of blood platelets in patients with hypertension]. / Funktsionalnoe sostoianie serotoninergicheskoi sistemy trombo- tsitov u bolnykh gipertonicheskoi bolezníu.

To investigate if there can be alterations in the 5-hydroxytryptamine (5-HT) uptake system in the sensitivity of platelets in patients with essential hypertension, 38 hypertensive patients and 37 normotensive healthy subjects were compared. In patients, the maximal 5-HT uptake velocity was reduced. The density of binding sites for 3H-imipramine was elevated in hypertensive females, but unchanged in males. The sensitivity of 5-HT uptake to trazodone was unchanged in patients. Half-maximal concentrations of 5-HT for inducing a shape change reaction of platelets were positively correlated with diastolic blood pressure in male patients and were reduced in female mild hypertensives. It is suggested that these changes are likely to be involved in the pathogenesis of hypertension.

Does platelet serotonin receptor supersensitivity accompany endogenous depression?

In a population of drug-free bipolar and unipolar depressed women, it was found that the concentration of serotonin sufficient to induce half-maximal shape change velocity in platelets is significantly (p less than 0.001) lower (0.13 +/- 0.0.04 microM) than that of closely matched controls (0.532 +/- 0.1 microM). This platelet concentration becomes higher after 1-3 months of antidepressant treatment (0.47 +/- 0.16 microM). Possible mechanisms for this up- or down-regulation of platelet serotonin receptor responsiveness are discussed.

[Activity of platelet serotonin receptors of patients with endogenous depression before and after treatment with antidepressive agents]. / Aktivnost' serotoninovykh retseptorov na trombotsitakh bol'nykh éndogennymi depressiami do i posle lecheniia antidepressantami.

Effective 5-HT concentration eliciting the half-maximal rate of platelet deformation (aggregation) in drug-free bipolar or unipolar depressed women was significantly (p less than 0.001) lower as compared with matched controls (0.13 +/- 0.04 microM and 0.532 +/- 0.1 microM, respectively). After 1-3 months of antidepressant treatment this value increased to 0.47 +/- 0.16 microM and was no longer different from control. Possible mechanisms controlling the activity of serotonin2 platelet receptors are discussed.

[Sensitivity of the retrograde uptake of H3-serotonin to imipramine and trazodone in patients with endogenous depression treated with antidepressive drugs]. / Chuvstvetel'nost' obratnogo zakhvata 3H-serotonina k imipraminu i trazodonu u bol'nykh endogennymi depressiiami pri lechenii antidepressantami.

The potency of imipramine (IMI) and trazodone (TRA) to inhibit (3H)-serotonin intake in unipolar and bipolar endogenous depressed patients (women aged 17 to 57 years) was evaluated before and during the antidepressant treatment. The potency of IMI was lower and that of TRA higher in patients as compared to controls. The both drugs' potencies became normal in patients treated with antidepressants. The significant decrease of imipramine binding sites density (Bmax) was evident after the treatment as against the normal levels. Significant correlation was observed between a severity of the patient's state evaluated using Hamiltone depression rating scale and the TRA potency but not IMI potency or Bmax. The data suggest different mechanisms regulating the serotonin uptake sensitivity to IMI and TRA. These are apparently involved in the pathogenesis of endogenous depression.

[Development of subsensitivity to imipramine in the system of reverse serotonin uptake by thrombocytes in patients with endogenous depression]. / Razvitie subchuvstvitel'nosti k imipraminu sistemy obratnogo zakhvata serotonina na trombotsitakh bol'nykh endogennymi depressiami.

The inhibitory effect of imipramine (IC50) on [3H]serotonin uptake and its kinetic parameter (V400) were measured in platelets of 9 patients with unipolar and 6 with bipolar affective disorder. The IC50 and V400 values in depressed patients were significantly higher (p less than 0.002) than these found in the control group. Treatment with antidepressants significantly decreased the IC50 values. The results support the hypothesis postulating that depression is related to a decreased modulatory capacity of imipramine binding sites and that the clinical effectiveness of these drugs is associated with the said modulatory capacity.

[Determination of the reversible uptake of 3H-serotonin in synaptosomes: an adequate evaluation of the contribution of nonspecific uptake]. / Opredelenie obratnogo zakhvata 3H-serotonina v sinaptosomakh: adekvatnaia otsenka vklada nespetsificheskogo zakhvata.

Serotonin (5-HT) uptake in synaptosomes was studied at 0 degree C (1), at 37 degrees C in the presence of 100 microM imipramine (IIa) or 100 microM zimelidine (IIb), in the absence of Na+ ions (III) in the incubation medium. A significant decrease (P less than 0.01) of the uptake rate has been found (III greater than IIa, b greater than I). Nonspecific uptake inhibition was thought to be the cause of these differences. Determination of specific uptake, using control III, has shown Na+-dependent transport of 5-HT only on the one type of carrier (Km = 174 + 24 nM). It is concluded that determination of 5-HT nonspecific uptake, using control III, has permitted a more exact evaluation of specific uptake parameters, than determination, using controls I and IIa, b.

[Inhibitors of reverse serotonin uptake and of specific imipramine binding in human blood plasma]. / Ingibitory obratnogo zakhvata serotonina i spetsificheskogo sviazyvaniia imipramina v plazme krovi cheloveka.

Human blood plasma contains low-molecular substances that inhibit in a dose-dependent manner both high-affinity specific binding of imipramine and reverse serotonin uptake by platelets. Incubation of human blood plasma with alumina was made use of to extract and study these imipramine-like inhibitors. The extract obtained from human blood plasma inhibited imipramine binding and reverse uptake of serotonin with median inhibitory concentrations of 0.18 +/- 0.1 and 0.36 +/- 0.15 mg/ml, respectively. After gel chromatography on Biogel P-2 the elution profile of the extract showed 2 major peaks of reverse serotonin uptake and imipramine binding inhibition and 3 additional peaks of reverse serotonin uptake inhibition, which did not have any considerable effect on imipramine specific binding. It is assumed that endogenous inhibitors of imipramine binding and reverse serotonin uptake are involved in the development of affective disorders.

Human plasma inhibitors of platelet serotonin uptake and imipramine receptor binding: extraction and heterogeneity.

Human plasma contains a considerable concentration of low molecular weight substances that inhibit, in a dose-dependent manner, both high-affinity imipramine receptor binding and serotonin uptake in platelets. Incubation of plasma with alumina was used to extract and to partly characterize these imipramine-like inhibitors. The human plasma extract inhibited imipramine binding and serotonin uptake with median inhibitory concentration (IC50) of 0.18 +/- 0.1 and 0.36 +/- 0.15 mg/ml, respectively. Imipramine-like activity of the extract was markedly degraded by carboxypeptidase B and leucine aminopeptidase, but was resistant to neurominidase and phospholipases A2, C, and D. The elution profile of the extract after gel chromatography on Bio-Gel P-2 showed two major peaks of serotonin uptake and imipramine binding inhibition and three additional peaks of serotonin uptake inhibitory activity that did not have a significant effect on imipramine binding. The possible mechanism of pharmacological action of the imipramine-like inhibitors and their relation to development of affective illnesses remain to be clarified.