[The effect of childhood stress on the development of mental disorders in adults].

There is evidence that not only severe stressful events, but also common low-threat events, in particular chronic ones, may cause or provoke some mental disorders. The literature data on the degree of pathogenicity of stress factors are insufficient. Authors attempted to summarize the established facts in the following aspects: current conceptions on the physiology and pathology of stress in the frames of the problem of psychosomatic disorders, deprivation in childhood, neurobiological consequences of childhood stress, psychiatric consequences of stress in childhood. Authors believe that this problem demands further investigation to find possible predictors of mental disorders in patients who had experienced stressful life events in childhood.

[Functions of microglia in the healthy brain: focus on neuroplasticity].

Microglia is in the center of modern research because it is involved in neuroinflammation processes, which is considered as an important part of pathogenesis of many brain pathologies. On the contrary, normal physiological functions of microglia are less studied. Here we review modern data on functioning of microglia in the healthy brain. We consider involvement of microglia in angiogenesis, neurogenesis, synaptogenesis, long-term potentiation, and the mechanisms of microglia-neuron interaction. We further consider modern concept on active interaction of microglia with neurons in developing and healthy mature brain and the essential role of microglia in neuroplasticity mechanisms at various levels.

[Molecular and cellular mechanisms of depression. Role of glucocorticoids, cytokines, neurotransmitters, and trophic factors in genesis of depressive disorders].

Here we review modern data on appearance and maintenance of depression at different levels of the body. We discuss a role of impairments of emotional and motivation mechanisms of adaptive behavior in genesis of depression. We demonstate an interaction of stress response and neuroinflammatory processes in pathogenesis of depression and analyze the effects of these molecular cascades on neurotrophic support of the central mechanisms of memory and neurogenesis.

[Role of NO/cGMP signaling cascade in the development of opium dependency].

This study was aimed at evaluating the role of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in mechanisms of morphine dependency formation. Morphine was introduced by intraperitoneal (i.p.) injections in rats twice per day over six days in doses increasing from 10 to 100 mg/kg, For evaluating the role of NO/cGMP cascade, NO synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME) was introduced (10 mg/kg, i.p.) 1 h prior to every injection of morphine. The L-NAME introduction led to enhancement of spontaneous withdrawal syndrome manifestations, which was accompanied by more pronounced decrease in the cGMP levels in midbrain and striatum. It is suggested that the region specific decrease in NO/cGMP cascade signaling activity in the brain can be among mechanisms determining the development of opium dependency.

[Effects of stress factors on adult hippocampus: molecular, cellular mechanisms and dorso-ventral gradient].

Adult hippocampus is one of the brain structures selectively vulnerable to stress factors. In the hippocampus, stress-induced neuroinflammation, neurodegeneration, epileptic activity and disturbances of neurogenesis take place. Stress of different modality specifically affects hippocampal structural and functional plasticity, the primary target of the stress hormones are corticosteroid receptors (glucocorticoid and mineralocorticoid receptors). Different parts of the hippocampus along the septo-temporal axis are functionally different. The dorsal hippocampus is in charge for definite forms of learning and memory, primarily spatial, while the ventral part is involved in stress response and anxiety behavior. Differences in basal and stress-induced molecular and cellular mechanisms of neuronal plasticity underlie this functional differentiation.

[Biomarkers in multiple sclerosis (a review and experimental data)].

Identification of biomarkers in multiple sclerosis is a very complex problem, and intensive work is being made in this field for the last decades. The importance of establishing biomarkers of multiple sclerosis is related to the high disease heterogeneity and lack of characteristic symptoms that leads to diagnostic, prognostic challenges and difficulties in making decisions about therapy. In this paper, we review the most important biomarkers and discuss their diagnostic and prognostic value. Experimental results on neurofilament heavy chains and antibodies to sulfatide in multiple sclerosis are presented.

[Neurodegenerative changes in rat hippocampal areas during the pentylenetetrazole kindling development].

The development of pentylenetetrazole-induced kindling is accompanied by neurodegeneration and neuronal loss in different areas of the hippocampus. However, the data on neurodegeneration development in the dentate gyrus remain controversial. In our study that was performed on 20 Wistar male rats, it was found that the process of neuronal loss was expressed unequally along the dentate gyrus. By the end of pentylenetetrazole kindling development, degenerating cells were present in the superior and inferior blades of the dentate gyrus, whereas the neuronal density in these areas was not reduced. On the other hand, in the angle of the dentate gyrus neuronal loss was already detected at the very early stages of kindling development. These findings allow to suggest a functional heterogeneity of a population of granule cells in relation to their susceptibility to seizure-induced injury.

[Involvement of Wnt signaling in hippocampal plasticity].

Wnt signaling is a signal transduction pathway involving peptides of Wnt family as key molecules. In this review, the data on the role of canonical and non-canonical Wnt pathway in hippocampal structural and synaptic plasticity have been analyzed. Wnt-mediated signal transduction is involved in normal functional plasticity, and the disturbances in Wnt-mediated mechanisms form a basis for the development of cerebral pathologies. A special attention is devoted to glycogen synthase kinase 3beta (GSK-3beta), one of most important from both plasticity and pathology perspectives component of the canonical Wnt pathway. The studies in this area, besides their fundamental significance, are important for translation to the medicine, and the key components of the Wnt pathway are potential targets for the developmentn of pathogenetical therapeutics for a number of socially significant cerebral pathologies.

[Evaluation of antiepileptic effects of cortexin in a model of convulsions].

We studied antiepileptic effects of cortexin administered in doses 0,015, 0,15 and 1,0 mg/kg intraperitoneally in solution or intranasally in the complex with nanoparticles in a model of acute and chronic convulsions in rats induced by pentylenetetrazole. In the model of epileptic status, the long-term preliminary administration of cortexin had no effect on convulsions while in the model of chronic convulsions (temporal epilepsy), cortexin had a marked dose-dependent antiepileptic effect. The influence of cortexin on neuroplasticity and its clinical potential are discussed.

[Remote control of the goal-directed behavior of freely moving rats by telestimulation of the rewarding brain structures].

The procedures are described that make it possible to train laboratory rats for remote control of their goal-directed behavior in open environments by telestimulation of rewarding brain structures. Rats were implanted electrodes in the lateral hypothalamus and lateral preoptic area. A week after surgery, rats were placed in an operant chamber and given electrical stimulation of increasing/decreasing intensity to each location to determine the most suitable site/hemisphere for reward delivery as well as the optimal stimulation parameters and the thresholds of behavioral reactions elicited. Then in T-maze, the animals were trained to obtain rewarding brain stimulation by running forward and turning correctly to the left or right arm of the maze in response to corresponding left- or right-turning light signal. At the last stage, rats were worn a backpack containing receiver-based remote-controlled microstimulator, connected to the implanted brain electrodes, and the animals were placed in open environments. The rewarding brain stimulation was delivered remotely using a transmitter connected to a laptop PC. Rats moved forward performing 'scanning' left-right head movements. Head movement in a desirable for the experimenter direction was reinforced. Animals remotely controlled by electrical stimulation of rewarding brain structures moved from one place of the environment to another according to any route given by an experimenter, overcame obstacles of different difficulties, not reacting to bright illumination, sounds and other external stimuli, and not exhibiting fear or curiosity, which are the typical reactions to novel surroundings. The more difficult was an obstacle the more stimulation was required to force an animal to overcome it.

[Akatinol memantine in patients with vascular cognitive disorders].

Treatment of cognitive disorders developed in cerebrovascular pathology is an actual medical problem. Of great importance is the timed diagnosis of these changes in the earlier phases of the development of cognitive deficit as well as adequate therapy that can delay and prevent the development of such complication as dementia. Pathogenetic mechanisms of cognitive disorders are associated with brain vascular and neurodegenerative changes that determine using drugs with vasoactive, metabolic and/or neuromediator effects. Memantine (the active component of akatinol memantine) is a drug that exerts an effect on the glutamatergic system, a non competitive antagonist of NMDA-receptors. The results of studies on the efficacy of this drug in moderate cognitive disorders are inconsistent and the amount of research is small. The present study aimed at the evaluation of changes of neuropsychological parameters in patients with moderate cognitive impairment caused by cerebrovascular pathology who were treated with memantine compared to the control group. Results of randomized open study suggested a significant clinical efficacy of akatinol memantine in the treatment of patients with vascular cognitive disorders. The treatment with akatinol memantine in dose 20 mg/day (10 mg twice a day) during six months significantly reduced cognitive deficit. The most distinct dynamics was related with ideation praxis, visual-spatial and speech functions, word selection, storage of instructions, increasing of volume of audio-speech and visual memory.

[Assessment of caspase-3 activity in rabbit myocardial tissue during experimental hemodynamic overload of the left ventricle of the heart].

It's well known that chronic overload of the cardiac left ventricle is accompanied by an increase in the cardiomyocyte apoptosis rate. However direction and extent of programmed cell death changes under an acute overload of the left ventricle still requires detailed investigation. Caspase-3 activity has been investigated in myocardium of rabbits on the 1, 3 and 5 days after modeling of left ventricle hemodynamic overload caused by surgical narrrowing of the ascending aorta. Control group included intact animals. It was found that caspase-3 activity significantly increased in both ventricles on day 1; it increased more than twofold above controls on day 3; it began to decrease by day 5. On the basis of the obtained data it was concluded that: an acute hemodynamic overload of the left ventricle is a cause of apoptosis acceleration in the myocardial tissue of both cardiac ventricles during first days of the investigated process.

[Active avoidance learning in rats and morphological changes in the hippocampus after pentylenetetrazole kindling].

The relationship between parameters of active avoidance conditioning and morphological changes in the hippocampus was investigated using pentylenetetrazole kindling animal model of epilepsy. Pentylenetetrazole kindling impaired learning of escape reaction and increased the number of intertrial crossings in a shuttle box during active avoidance conditioning. Kindling decreased the number of neurons in the hippocampal CA1 and CA3 fields and in the dentate gyrus and increased the number of abnormally changed neurons, which displayed cell shrinkage and chromatophilic staining. Negative linear correlations were found between seizure severity and the number of normal neurons in the hippocampus (CA1 and CA3) and dentate gyms in the kindled rats. Positive correlations between the number of damaged neurons and seizure severity were revealed in the CA1 field of the hippocampus and dentate gyrus in the same group. No correlations could be found between the seizure score or behavioral indices in the active avoidance test, or between the indices of the active avoidance learning and the number of undamaged cells in the hippocampus. However, in the control animals, negative correlations were demonstrated between the number of damaged cells in the CA1 and CA3 field and the number of avoidance reactions in the first and last learning sessions.

[Caspase-3 activity in the rat hippocampal slices reflects changes in synaptic plasticity].

Considering the involvement of caspase-3 in neuronal plasticity, we studied caspase-3 activity in the rat hippocampal slices, and electrophysiological characteristics of extracellular responses to paired-pulse stimulation of Schaffer's collaterals in the CA1 subfield of hippocampus. Caspase-3 activity was measured after electrophysiological recording in each slice separately. Maximal caspase-3 activity was observed in the slices with low responsiveness to single afferent stimulation indicative of decreased efficacy of interneuronal interaction. This phenomenon is unrelated to depression of neuronal excitability since paired-pulse stimulation increases the synaptic efficacy to second stimulus thus restoring population spike amplitudes to normal values. In "damaged" slices with impaired spike generation up to disappearing spikes to both stimuli, caspase-3 activity was close to the normal level of the "healthy" slices. The activity of another proteinase, cathepsin B, was increased in the "damaged" slices, no correlation with the modifications of electrophysiological indices being detected. Our data suggest that high caspase-3 activity in hippocampal slices is involved in maintenance of synaptic plasticity but not necessarily related to apoptosis.

[Epileptic seizures in patients with stroke: risk factors and mechanisms of their development].

The current state of the problem of epileptic seizures developed after ischemic and hemorrhagic stroke is presented. Etiology, pathogenesis risk factors of epileptic seizures and their impact on the course and severity of stroke are reviewed. It has been shown that "early" and "late" epileptic seizures have different mechanisms of development. The authors consider the impact of single and serial epileptic seizures on the outcome of the disease.

[Anxiety level during morphine abstinence correlates with the status of nitrergic system in the rat hippocampus].

Opiate addiction is accompanied by long-term structural and functional changes in brain regions persisting during abstinence, this status being an experimental model of the aberrant neuroplasticity. Nitric oxide is known to be involved in mechanisms of psychopathological events during opiate abstinence. In this study, indices of a nitregic system (nitric synthase activity--NOS, nitrites and nitrates concentration--NOx-) were measured in the rat brain region during morphine abstinence. Prior to this, the rats were tested for anxiety in an elevated plus maze. NOS activity increased in hippocampus 3 days after morphine withdrawal, while NOx--6 days after withdrawal. No changes of the nitrergic system could be revealed in other brain regions under study. Six days (but not 3 days) after morphine withdrawal, rats visited the open arms of the plus maze more frequently and spent more time in these arms as compared with respective controls. The data suggest that nitrergic system changes in the hippocampus may be involved in molecular mechanisms of behavioural alteration during morphine abstinence in rats.

[Developmental caspase-3 activation in the rat hippocampus is involved in the maturation of instrumental behavior].

Previously the developmental switch to caspase-3 activation in the rat hippocampus has been shown during the third week of life. The goal of this study was to explore effects of caspase-3 inhibition during this period on learning in a two-way avoidance paradigm. On postnatal day 18, the pups were intracerebroventricularly administered with caspase-3 inhibitor Z-DEVD-FMK. Control groups were injected with either the control peptide Z-FA-FMK or saline. Caspase-3 inhibition, naturally activated in this critical period, was found to disturb the maturation of instrumental behavior. In particular, the young adult rats of Z-DEVD-FMK group displayed less effective elaboration of escape and active avoidance reactions in two-way avoidance paradigm, accompanied with a decrease in inter-trial crossings. However, associative components of the learning did not change after caspase-3 inhibition. Conditioned emotional behavior was, in general, similar in all groups, and the number of responses related to conditioned stimulus exploration did not differ in Z-DEVD-FMK and Z-FA-FMK groups. In spite of the deficit in active avoidance conditioning in Z-DEVD-FMK group, a significant increase in incomplete or preparatory reactions to conditioned stimulus was demonstrated suggesting that the association between predictive conditioned stimulus and possibility of crossing can be elaborated. The change of exploratory behavior is unlikely to be specific for caspase-3 inhibition, being similar in Z-DEVD-FMK and Z-FA-FMK groups.

[Kindling during early postnatal development: the effects on the maturation of the hippocampal electrophysiological characteristics].

The effect of repeated pentylentetrazole (PTZ) administration on the postnatal development of hippocampal electrophysiological indices has been studied. Contrary to adult rats, repeated PTZ injections did not intensify convulsive activity in rat pups (from postnatal day 14). We did not observe any between-group differences in population spike amplitudes and paired pulse facilitation (PPF) ratio at 70 ms interpulse interval during early period of postnatal development, PPF suppression at short interlulse interval (15 ms) only was significantly less in PTZ group as compared with saline-injected controls, but the effect of saline injections has developed in the same directio However PTZ resulted in the modification of developmental profile. Besides the change of paired-pulse inhibition (15 ms), in the slices of young rats (27-48 postnatal days) the input-output curve was specifically modified and the intensity-dependent increase in population spike amplitudes was less expressed than in the slices of young control rats repeatedly subjected to saline injection, while PPF ratio of both groups was significantly decreased in a similar way, as compared with passive controls. In addition, LTP magnitude in the slices of PTZ group was also suppressed. These modifications did not correlate with convulsive activity. A significant correlation with convulsive activity was found only for population spike amplitudes evoked by low, near-threshold stimuli.

[Nitric oxide synthase activity and nitrates/nitrites level in brain regions during the spontaneous morphine withdrawal in rats].

Nitric oxide synthase (NOS) activity and nitrate/nitrites (NO(x)-) concentrations were measured in brain regions of rats during the spontaneous morphine withdrawal. Male Wistar rats were injected intraperotoneally with morphine hydrochloride at increasing doses (10-100 mg/kg) during 6 days twice a day. Thirty six hours after the last injection the severity of the spontaneous morphine withdrawal syndrome was determined by specific autonomic and locomotor indices. Both NOS activity and NO(x)- levels increased in the midbrain and the hippocampus, decreased in the striatum and the hypothalamus, and did not change in the cerebral cortex and the brain stem. NO(x)- concentrations in the cerebellum did not change, while NOS activity decreased. Both NOS activities and NO(x)- concentrations in the cerebral cortex, striatum, midbrain, and cerebellum correlated with withdrawal syndrome severity on the whole, and with the specific signs of abstinence.

[Effects of intracerebroventricular administration of a caspase-3 inhibitor Z-DEVD-FMK on behavior of rats].

Rats received intracerebroventricular injections of z-DEVD-FMK (caspase-3 inhibitor) or z-FA-FMK (control peptide) in a dose of 3 nmol. Administration of z-DEVD-FMK significantly decreased the number of avoidance reactions in some blocks of trials in active avoidance (shuttle box) learning. However, only slight effect of the caspase inhibitor across the session was found. Z-DEVD-FMK impaired development of some essential components of the two-way active avoidance performance, such as escape reaction, conditioned fear reaction, and inter-trial crossings. Z-DEVD-FMK did not impair working memory in the spontaneous alternation behavior paradigm. Z-DEVD-FMK affected neither emotionality nor locomotor activity in the open-field test. It also did not influence behavior in the light-dark chamber. Measurement of caspase-3 activity in rat brain regions involved in active avoidance learning revealed z-DEVD-FMK-related inhibition of the enzyme activity most pronounced (about 30%) in the fronto-parietal cortex; a similar effect was close to significant in the hippocampus. The results suggest the involvement of brain caspase-3 in selected forms of learning.