[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.

[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.

[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.

[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.

[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.

[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.

[Pentylenetetrazole kindling in rats: whether neurodegeneration is associated with manifestations of seizure activity?].

Structural changes in neurons and oxidative stress in hippocampus were studied in rats "tolerant" (TR) and susceptible (SR) to tonic and clonic seizures in pentylenetetrazole (PTZ) kindling. The number of normal neurons was significantly decreased in CA1 subfield of TR hippocampus after 11 injections of PTZ, while in SR neuronal cell loss was evident in CA1 and fascia dentata. In both groups, neuronal cell loss was accompanied by increase in damaged neuron number in CA4 subfield. After 21 injections of PTZ, the decrease in normal neuron number was revealed in CA1 subfield of both TR and SR, while the number of damaged neurons was above the control level in hippocampal subfields CA1 and CA4 in TR only. Glutathione level was decreased in hippocampus of both TR and SR as compared with control rats. Thus, rats tolerant to PTZ-induced convulsions demonstrated oxidative stress and neurodegeneration in hippocampus. The results suggest that, in PTZ kindling model, oxidative damage of neurons resulting in neurodegeneration in hippocampus is not directly related to the convulsive activity.

[Effects of central administration of beta-amyloid peptide (25-35): pathomorphological changes in the hippocampus and impairments of spatial memory]. / Issledovanie éffektov tsentral'nogo vvedeniia beta-amiloidnogo peptida (25-35): patomorfologicheskie izmeneniia v gippokampe i narushenie prostranstvennoi pamiati.

A possible relationship between the amnesia induced by central administration of beta-amyloid (25-35) [Abeta(25-35)] and neurodegeneration in the hippocampus was studied. Male Wistar rats received a single intracerebroventricular injection of Abeta(25-35) at a dose of 15 nmol. One month after the administration, animals were trained in an eight-arm radial maze. After the training, a histopathological investigation of the hippocampus was carried out using brain slices stained with hematoxylin/eosin. Abeta(25-35) induced impairments in reference and working memory in the eight-arm radial maze. A moderate decrease in neuronal cell number was demonstrated in the CA1, but not in the CA3 subfield of the hippocampus. The number of both reference and working errors negatively correlated with the number of neurons in hippocampal CA1. The results are the first evidence for a specific relationship between neurodegeneration in the CA1 subfield of rat hippocampus and impairments of learning and memory induced by Abeta(25-35).

[Effects of amyloid beta peptide (25-35) on the behavior of rats in a radial maze]. / Issledovanie vliianiia fragmenta (25-35) beta-amiloidnogo peptida na povedenie krys v radial'nom labirinte.

Impairment of cognitive functions, particularly long-term (episodic) and working memory, is one of the earliest prognostic symptoms of Alzheimer's disease, both cognitive impairment and neurodegeneration being mediated by amyloid-beta neurotoxicity. Effects of intracerebroventricular administration of amyloid-beta peptide (25-35) [A beta(25-35)] to rats on the retention of previously learned task in an 8-armed radial maze was studied. A beta(25-35) was injected bilaterally, at doses of 15 or 30 nmol/rat, 7 days after the preliminary learning. The performance in the maze was tested 60 days after the surgery. A beta(25-35) impaired the short-term memory, with no significant effect on the long-term memory. No dose dependence could be demonstrated.

[Electroconvulsive shock causes neuronal death in the mouse hippocampus: correlation of neurodegeneration and convulsive activity]. / Elektrokonvul'sivnyi shok vyzyvaet gibel' neironov v gippokampe myshei: korreliatsiia neirodegeneratsii s sudorozhnoi aktivnost'iu.

Relations between seizures induced by repeated electroshock (ES) and structural changes in the hippocampus were investigated in Balb/C mice. Brain sections of the animals 2 or 7 days after the last ES were stained for Nissl or TUNEL (apoptotic nuclei). Direct measurement of caspase-3 activity (a key enzyme of apoptosis) in brain regions was performed immediately after the last ES. Statistically significant, albeit moderate cell loss was demonstrated in the CA1 field and dentate gyrus, but not in the CA3 field of the hippocampus. The number of neurons in these fields inversely correlated with seizure severity. No apoptotic nuclei could be revealed either in hippocampus or in other brain regions. Caspase-3 in the hippocampus decreased after ES. The data obtained support the results from other groups showing prominent functional changes in neurons induced by repeated ES and extend this concept directly testifying for a moderate (within 10%), albeit statistically significant neuronal death in selected hippocampal fields. The inverse correlation of cell number with severity of seizures suggest that these are seizures inducing neuronal death.

[Effects of morphine withdrawal on the indices of free radical homeostasis and nitric oxide system in rat liver and thymus]. / Vliianie sindroma otmeny morfina na pokazateli svobodnoradikal'nogo gomeostaza i sistemu oksida azota v pecheni i timuse krys.

Indices of oxidative stress, nitric oxide (NO) metabolism as well as the activity of caspase-3, an important enzyme of apoptotic cell death, were measured during the morphine withdrawal syndrome in liver and thymus of rats. Male Wistar rats were administered with morphine hydrochloride (i.p., at increasing doses from 10 to 100 mg/kg, twice a day, for 6 days). Thirty-six hours after the last administration the withdrawal syndrome was monitored using the specific autonomic and locomotor indices. During this period, weights of body and thymus significantly decreased. Oxidative stress in liver was accompanied by an increase in aspartate aminotransferase and gamma-glutamyl transferase in blood serum. No signs of oxidative stress could be demonstrated in thymus. The activity of the Ca(2+)-dependent isoform of nitric oxide synthase (NOS) in liver increased, while, the activity of the Ca(2+)-independent NOS diminished, the total activity of NOS in liver and thymus remained unchanged. The concentration of nitrates/nitrites in blood was decreased, in thymus increased, and in liver unchanged. Caspase-3 activity changed neither in liver, nor in thymus. The results are discussed from the perspective of possible antioxidant and antiapoptotic role of NO during morphine withdrawal syndrome.

[Pentylenetetrazole kindling induces caspase-3 activation in rat brain]. / Pentilentetrazolovyi kindling vysyvaet aktivatsiiu kaspazy-3 v mozge krys.

Pentylenetetrazole kindling (but not a single pentylenetetrazole injection) induced caspase-3 activation in the cerebral cortex, hippocampus, and cerebellum of rats as well as neurodegeneration in the hippocampus. The number of neurons in the CA3 subfield of the hippocampus decreased significantly, whereas no apoptotic nuclei could be detected. The results support a possible non-apoptotic involvement of caspase-3 in brain plasticity.

[Analysis of the level of cyclic adenosine-3',5'-monophosphate in structures of the 'informational' and 'motivational' system of the rat brain during active conditioning]. / Analiz soderzhaniia tsiklicheskogo adenozin-3',5'-monofosfata v strukturakh "informatsionnoi" i "motivatsionnoi" sistem mozga krys pri vyrabotke uslovnoi reaktsii aktivnogo izbeganiia.

The content of cyclic adenosine-3',5'-monophosphate (cAMP) was studied in structures of the "motivational" and "infromational" systems of rat brain after the active avoidance conditioning procedure in rats. Three groups of animals were examined: naive rats, trained (conditioned) rats, and group of the active control presented with uncombined conditioned (light) and unconditioned (electric footshock) stimuli. The content of cAMP was determined in the frontal cortex, hippocampus, amygdala, and hypothalamus of both hemispheres immediately after the retrieval of conditioned reaction one day after conditioning. A significant increase in cAMP level was bilaterally observed in the hypothalamus in the group of active control, and in both hippocampi and the right frontal cortex in the conditioned animals. Positive correlations between the cAMP levels in symmetrical regions of the frontal cortex, amygdala, and hypothalamus were revealed in all the examined groups. Additionally, intra- and interhemispheric correlations were found in the active control and conditioned rats. Patterns of correlation were specific for each of these groups. The observed phenomenon is discussed in term of involvement of "informational" and "motivational" brain structures in the mechanisms of adaptive behavior.

[Administration of aggregated beta-amyloid peptide (25-35) causes change in long-term potentiation in the hippocampus]. / Vvedenie agregirovannogo beta-amiloidnogo peptida (25-35) vyzyvaet izmenenie dlitel'noi potentsiatsii v gippokampe in vivo.

A month after intracerebroventricular injection of aggregated beta-amyloid fragment 25-35 (7.5 nmol/ventricle), a significant change in in vivo long-term potentiation in hippocampus was demonstrated. The time course of the long-term potentiation was compared with that in sham-operated animals, a powerful and stable increase in the evoked potential amplitude was observed. This phenomenon can be related with the oxidative stress that was revealed in this model in our previous studies, and, as a consequence, with deterioration of ion homeostasis.

[The effect of oxidative stress on brain nitric oxide synthase activity in vivo and in vitro]. / Vliianie okislitel'nogo stressa na aktivnost' sintazy oksida azota mozga in vivo i in vitro.

Within 8 days of a 10-min cardiac arrest, accumulation of material reacting with 2-thiobarbituric acid was revealed in the hippocampus (74%) and cerebellum (47%) of male Wistar rats. Oxidative stress was accompanied by a twofold decrease of the nitric oxide synthase activity in the brain tissue. In vitro experiments showed a dose-dependent decrease of nitric oxide synthase activity in the brain homogenates as a result of the oxidative stress induced by hydrogen peroxide or sodium hypochlorite. The findings suggest that the oxidative stress may decrease nitric oxide synthase activity as a result of direct effects of the active oxygen on the enzyme.

[The delayed effects of systemic circulatory arrest on the free-radical processes in the brain structures of rats with different types of behavior in the emotional resonance test]. / Otsrochennye éffekty ostanovki sistemnogo krovoobrashcheniia na svobodnoradikal'nye protsessy v strukturakh mozga krys s raznymi tipami povedeniia v teste émotsional'nogo rezonansa.

Male Wistar rats with different types of behavior in "emotional resonance" test ("active" and "passive") were studied one week after the global ischemia induced by cardiac arrest. Recovery of some physiological functions as well as free-radical-mediated processes and NO-synthase activity were studied in cerebral structures and blood serum. The "open-field" behavior normalized more rapidly in the "active" rats than in the "passive" ones, though the time course of the neurologic deficit compensation did not differ in these groups. A decrease in superoxide scavenging activity and in the content of 2-thiobarbituric acid-reactive material was revealed in the cerebral structures of both "active" and "passive" rats. Increased levels of free-radical generation in the hippocampus of the "passive" rats and in the cerebellum of the "active" rats were found. Higher NO-synthase activity was demonstrated in the cerebellum of the "passive" rats. Taken together, these data suggest that there are specific patterns of free-radical-mediated processes in the brain of rats with different types of behavior in "emotional resonance" test.

The effect of systemic circulatory arrest on the process of free-radical oxidation and on NO-synthase activity in the brain structures of rats of different behavioral types in an emotional resonance test: the acute effects. / Vliianie sistemnoi ostanovki krovoobrashcheniia na protsessy svobodnoradikal'nogo okisleniia i aktivnost' NO-sintazy v strukturakh mozga krys s razlichnymi tipami povedeniia v teste émotsional'nogo rezonansa: ostrye éffekty.

Free radical-mediated processes and NO-synthase activity were studied in cerebral structures and blood serum of male Wistar rats with different types of behavior in emotional resonance test one hour after global ischemia induced by cardiac arrest. Oxidative stress accompanied by loss in NO-synthase activity was revealed in cerebral cortex after the ischemia. The oxidative stress was also evident in cerebellum and to a lesser extent in hippocampus. The majority of behavior-related biochemical differences were induced by cardiac arrest. These differences could be global or related to specific brain structures. Sometimes they became apparent in cerebral lateralization of biochemical indices.