IN SILICO PROFILING OF THE NEW ALLOSTERIC MODULATOR OF AMPA RECEPTORS.

The aim of this study is to investigate the computer-aided prediction of pharmacological activity and mechanisms of action of 6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trione (TCT-9). The compound was designed for modulation of ionotropic glutamate AMPA receptors, and its affinity for the receptor has been earlier proven experimentally. A cognitive stimulating effect of TCT-9 has been shown using a model of freezing behavior in mice. The drug candidate TCT-9 is now under the development process: it is intended for the treatment of cognitive impairments in case of brain injury. Following the existing requirements, the present study was carried out in the framework of secondary pharmacodynamic studies to determine possible off-target effects and interaction of the compound with regulatory signaling and metabolic networks/pathways. In silico study of the TCT-9 binding to pharmacologically significant targets and the new AMPA receptor modulator's effects on signaling pathways was carried out by the analysis of structure-activity relationships. Prediction of biological activity spectra was performed using PASS (Prediction of Activity Spectra for Substances), which estimates the probabilities for more than five thousand biological activities. The PharmaExpert program assessed information on the belonging of the targets predicted by the PASS program to the signaling and metabolic pathways. The prediction results are the basis for the experimental verification of the binding of the TCT-9 to the steroid hormone receptor ERR1 and further studies of the drug activity in animal models of diseases.

[Possible use of the growing liver biological set for hepatic recovery after toxic damage (an experimental study)]. / Vozmozhnosti biologicheskoi kombinatsii, poluchennoi iz rastushchei pecheni, dlia ee vosstanovleniia pri toksicheskom povrezhdenii (éksperimental'noe issledovanie).

The lack of acceptable pharmacological approaches for restoration of the injured liver is associated with complex of mechanisms involved in hepatic regeneration and with difficulty of the target selection. The aim of this research was to study the hepatoprotective function of the extract from both the growing and regenerating liver containing a natural set of factors crucial for the hepatic restoration. Extracts from both regenerating liver of rats after 70% hepatic resection and the growing liver of neonatal pigs were obtained using own original technique. The set of resultant extracts was named as the hepatic regeneration set (HRS). HRS fractionation was carried out using the Toyopearl HW-50S sorbent. The efficiency of HRS and its fractions was estimated using a model of the mouse liver thioacetamide injury and monitoring hepatic enzyme activity in blood serum. The activities of AST and ALT in intact animals were 50 U/l and 80 U/l, respectively; after thioacetamide administration they increased to 2059±212 U/l and 4280±440 E/l, respectively (p<0.05). Treatment of injured animals with HRS from the rat regenerating liver resulted in a significant decrease of transaminase activities to 924±148 U/l (AST; p<0.05) and 1633±308 U/l (ALT; p<0.05). A similar effect was observed after treatment with HRS from the neonatal pig liver: the AST decreased to 937±138 U/l (p<0.05), while ALT activity decreased to 1710±237 U/l (p<0.05). HRs fractionation resulted in identification two active fractions characterized by much higher (8-29) hepatotropic effect that that of the whole extract. These fractions contained peptide/protein components with the range of molecular mass of 3-60 kDa (fraction 1) and 3-25 kDa (fraction 2a). Fraction 1 also contained some polynucleotides in fraction 1. Subsequent studies of these fractions exceeding the hepatotropic effect of original HRS is clearly needed to identify their individual components by immunochromatography methods, ELISA, MRM mass spectrometry and quantitative PCR.

[Molecular-genetic and electroencephalographic markers of neurocognitive processes in depressive disorders].

Perspectives of molecular-genetic approaches to the establishment of mechanisms of development and causes of heterogeneity of neurocognitive impairment are discussed. The current results indicate that candidate genes for depression can contribute to the variance of memory and regulatory functions in patients. At the same time, these genes are closely related to affective information processing and .cortisol level. By that fact, it can't be excluded that affective processes moderate the association between cognition and genes. EEG parameters could be useful phenotypes in the search for and understanding of genetic mechanisms of cognitive deficit in depression. Parameters of resting EEG and its reactive changes are known to reflect the certain cognitive processes. They are influenced by genetic factors and are sensitive indicators of mechanisms that might underlie cognitive impairment in depressive patients. Accumulating data on molecular-genetic correlates of normal electric brain activity may be a source of choosing new candidate genes for cognitive impairment in depression.

[EEG spectral characteristics in resistant depression patients on transcranial magnetic stimulation treatment].

OBJECTIVE: to examine the EEG spectral characteristics during TMS in resistant depression therapy. MATERIAL AND METHODS: The sample consisted of 32 depressive patients diagnosed with recurrent depressive disorder or bipolar affective disorder. TMS, as well as EEG, were conducted during the previous inefficient thymoanaleptic therapy with reduced doses. TMS was performed in the left prefrontal cortex. Treatment course consisted of 15 procedures with 100% threshold intensity. During a single procedure, the patient received 20 cycles of stimulation pulses with the frequency of 15 Hz, duration of 20 seconds and interval of 60 seconds between single cycles. EEG was recorded with the use of the «NEURO-KM¼ apparatus (Russia) with band pass from 0.5 to 45 Hz and time constant of 0.3 sec before and after the course of TMS. Spectroscopic analysis of EEG was conducted using the Fast Furies Transformation analysis with average of no less than 30 periods for 2 seconds with subsequent mapping with the use of the «BRAINSYS¼ system (Russia). RESULTS AND CONCLUSION: After conducting TMS, EEG changes were generalized and included the reconstruction of all frequencies of the electrical brain activity. However, the major changes were seen in alpha-rhythm spectrums: its index increased in all cortical areas, mostly in the occipital cortex, thereby forming the alpha-rhythm focus in these areas.

[Diurnal dynamics of the reactivity to stress-test in patients with depression].

The aim of the work was to study the responses to the stress-test (a threat of painful stimulation) in patients with depressive disorders during the day using encephalography with coherence analysis (COH). The difference in averaged records (stress test - background) over all cortical areas had positive values in the morning (from 8 to 10 am) and in the evening (from 4 to 6 pm) that reflected the generalized enhancement of the functional activity of cortical areas of both hemispheres. The highest value of the difference was observed in the left hemisphere in the morning hours, the lowest - in the right hemisphere in the evening records. The response to the stressful situation in the left hemisphere in the morning and in the evening varied. In the morning, the increased functional activity in frontal, middle- and posttemporal temporal EEG was observed while the weaker activity was seen in the central and occipital areas. In the evening, there was the diffuse increase in the functional activity.

Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor.

Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.

beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern.

Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.

[Special features of autonomic regulation in patients with seasonal depression]. / Osobennosti vegetativnoi reguliatsii u bol'nykh sezonnymi depressiami.

Parameters of histograms distribution of ECG R-R intervals (the mode, mode amplitude, variation range) were compared in 60 healthy individuals and 45 patients with seasonal depressions. These ECG parameters reflect influence of sympathetic and parasympathetic parts of the autonomic nervous system on the rhythms of cardiac contractions. In the period of active development of depressive symptomatology the parameters of histograms in terms of R-R distribution were changed in comparison with the healthy individuals: mode was displaced to the region of the short intervals, the mode amplitude was increased and the variation range was reduced. All these data indicate increase of the sympathetic activity and reduction of parasympathetic activity as compared with the control individuals. In the patients with spring-summer depressions the determined parameters of autonomic nervous system were more changed than in the patients with autumn-winter depressions. Under the course of pharmacotherapy the dynamics of these parameters was less marked in patients with fall-winter depressions than in cases of spring-summer depressions.

[Dynamics of ECG changes during the treatment of depressive conditions with different variants of the course of endogenous affective psychosis]. / Dinamika izmenenii EKG pri lechenii depressivnykh sostoianii u bol'nykh s raznymi variantami techeniia éndogennogo affektivnogo psikhoza.

The ECG parameters were studied and compared in normal subjects and patients suffering from affective psychosis running bi- and monopolar course during the development of the depressive phase and after its removal. At the prodromal stage before treatment, the patients manifested sinus tachycardia, changes in the ST configuration and QRS complex. On the histograms of RR intervals distribution, the modal value was shifted to the area of short intervals, the mode amplitude was higher whereas the variation range was more narrow than in the healthy subjects. Intergroup comparisons of the changes in the ECG parameters have shown that the disturbances were more remarkable in the patients with bipolar psychosis. At the initial stage of the treatment with antidepressants, the disorders were either unchanged or got intensified. The initial positive changes in the study parameters were seen only in the presence of the initial clinical improvement. However, the intergroup differences increased at the same time. The removal or appreciable reduction of the psychopathological symptomatology revealed a reversible nature of the changes in myocardial depolarization and disorders of conduction within the system of His bundle crura, seen before treatment. Still, the patients continued manifesting sinus tachycardia and changes in the cardiointerval histograms, particularly those with monopolar depressive psychosis.