Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

Memantine attenuates cognitive impairments after status epilepticus induced in a lithium-pilocarpine model.

The capability of memantine, a noncompetitive antagonist of the NMDA receptors, to prevent impairments of cognitive functions in rats was investigated in the lithium-pilocarpine model of epilepsy. After status epilepticus, rats exhibited impaired exploratory behavior and spatial memory, and a decline of extinction of orienting behavior. Memantine administration prevented these disturbances. Thus, the blockade of the NMDA receptors immediately after status epilepticus allowed prevention of the development of the possible cognitive impairments.

[EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS IN ADULT RATS AFTER ADMINISTRATION OF INTERLEUKIN-1beta DURING DIFFERENT PERIODS OF EARLY LIFE].

Multiple sclerosis is a chronic disease of the CNS that affects people of working age, in which the targets of aggressive immune cells become the myelin and myeline producing cells, as well as neurons. It is assumed that a predisposition to MS is forming in childhood, due to common infections. In this paper the experimental allergic encephalomyelitis (EAE) was examined in rats administered IL-1beta at different periods of the early postnatal ontogenesis. EAE was induced in rats at the age of 3 months by single subcutaneous immunization with a homologous homogenate of spinal cord in complete Freund's adjuvant. The number of sick animals were evaluated, as well as the severity of the disease and its duration. It was shown that in rats after administration of IL-1beta on 1st and on 4th week of life EAE is more severe than corresponding control groups of rats. Discusses the damaging or protective effects of injections of IL-1beta during different periods of early postnatal ontogenesis, role of stress reactivity and communication with the "hygiene hypothesis".

Impairment of exploratory behavior and spatial memory in adolescent rats in lithium-pilocarpine model of temporal lobe epilepsy.

Cognitive impairment in six-week -old rats has been studied in the lithium-pilocarpine model of adolescent temporal lobe epilepsy in humans. The pilocarpine-treated rats (n =21) exhibited (a) a decreased exploratory activity in comparison with control rats (n = 20) in the open field (OP) test and (b) a slower extinction of exploratory behavior in repeated OP tests. The Morris Water Maze (MWM) test showed that the effect of training was less pronounced in the pilocarpine-treated rats, which demonstrated disruption of predominantly short-term memory. Therefore, our study has shown that lithium-pilocarpine seizures induce substantial changes in exploratory behavior and spatial memory in adolescent rats. OP and MWM tests can be used in the search of drugs reducing cognitive impairments associated with temporal lobe epilepsy.

[THE EFFECTS OF CHRO- NIC ADMINISTRATION OF MODERATE DOSE OF PROINFLAMMATORY CYTOKINE INTERLEUKIN-1ß ON RAT INVESTIGATIVE BEHAVIOR AND SPATIAL MEMORY].

The aim of this study was to discover the effects of chronic intraperitoneal administration of proinflammatory cytokine interleukin-1ß (IL-1ß) on rat investigative behavior and spatial memory. Rats were injected with a moderate pyrogenic dose of IL-1ß (0.5 mkg/kg) daily during 14 days (7 days before tests and 7 testing days). The behavior was examined in 23.5 hours after the previous injection of cytokine. The test battery included: "The open field" (within 3 consecutive days), "The exploration of novel objects", and "The Morris water maze". The animals treated with IL-1ß differed from the control animals in an essential decrease of locomotor activity, slight increase of anxiety and suppression of exploratory behavior. The impairment of spatial memory was not revealed.

Behavioral, hormonal, and neurotransmitter reactions to stress in adult rats with a history of high IL-1ß content in the early postnatal ontogeny.

Behavioral, hormonal, and neurotransmitter reactions to foot shock were studied in adult rats treated with IL-1ß during week 3 of life. After stress, these animals differed from controls treated with saline by high levels of dopamine, serotonin, and 5-hydroxy-indolacetic acid in the hypothalamus. In contrast to controls, they developed a significant stress-induced increase of blood corticosterone level and exhibited lesser motor and exploratory activities in the open field test.

[The administration of interleukin-1beta during early postnatal develop ment impairs FGF2, but not TIMP1, mRNA expression in brain structures of adult rats].

According to the Neurodevelopmental hypothesis, the long-lasting cognitive deficit in schizophrenia and other types of neuropathology may occur by injurious factors, such as hypoxia, traumas, infections that take place during pre- and postnatal development, at least at early stages. These pathological conditions are often associated with the high production of pro-inflammatory cytokine interleukin-1B (IL-1B) by the cells of immune and nervous systems. We investigated the expression of genes involved in the neuroplastic regulation (Fgf2 and Timp2) in medial prefrontal cortex and dorsal and ventral regions of hippocampus of adult rats that were treated with IL-1beta between P15 and P21. The learning impairment in IL-1beta-treated rats is accompanied by lower FGF-2 mRNA levels in medial prefrontal cortex and ventral (not dorsal) hippocampus, but TIMP-1 was not affected. No differences in TIMP-1 and FGF-2 mRNA expressions were observed in untrained IL-1beta-treated when compared to control rats.

[The influence of neonatal interleukin-1beta increase on the formation of adult rats' spatial memory].

Children's and adults' cognitive dysfunctions are frequently caused by various types of pathology such as birth injuries, hypoxias, and infections suffered in prenatal and early postnatal periods of ontogenesis. These abnormal conditions trigger high production of proinflammatory cytokines by the cells of nervous and immune systems. The role of interleukin-1 beta (IL-1beta), one of such proteins, in the formation of cognitive deficit in early ontogenesis is not sufficiently studied. In present research it was revealed that administration of IL-1beta during the third week of postnatal ontogenesis impaired the learning of adult rats in Morris Water Maze. The differences between rats of control and experimental groups were observed during the training of searching for hidden platform and during the alteration of formed reflex (when the platform was in a different place). Meanwhile the spatial extinction has not been disrupted. The nature of experimental rats' learning abnormalities allows us to assume that the mechanisms of long-term but not short-term spatial memory are damaged in this experimental situation.

[Impairments of conditioned behavior in adult rats induced by interleukine-1beta treatment in early postnatal ontogenesis].

Impairments of cognitive functions in children and adolescents are often consequences ofperinatal pathology (natal injuries, ischemia, hypoxia, infection and allergic diseases), which are accompanied by enhanced production ofproinflammatory cytokine interleukine-1beta. In this work it was shown that treatment with interleukine-1beta during the third week of life impaired active and passive avoidance conditioning in adult rats at the age of 60-70 days.

Long-term disorders of behavior in rats induced by administration of tumor necrosis factor during early postnatal ontogenesis.

The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) is one of the main mediators of neuroimmune interactions. Increased production of TNFalpha in nerve and immune system cells occurs in infectious diseases, traumas, ischemia, and hypoxia. The present study addressed the role of TNFalpha in the formation of behavior during early postnatal ontogenesis. TNFalpha was given to rats during the third week of life and behavior was tested at ages 1.5 and 3 months using the open field test and the elevated plus maze test. Experimental rats differed from controls in terms of changes in orientational behavior on testing at 1.5 months and an increase in anxiety on testing at 1.5 and 3 months. The different roles of proinflammatory cytokines in the brain at the early stages of ontogenesis are discussed.

[Long-term disorders in the rat behaviour induced with introduction of the tumour necrosis factor in early postnatal ontogenesis].

Anti-inflammatory cytokin the tumour necrosis factor alpha (TNFalpha) is one of the main mediators of neuroimmune interactions. The TNFalpha production increase in the cells of neural and immune systems occurs in infectious diseases, injuries, ischemia, hypoxia. In this study, the TNFalpha revealed its role in formation of behaviour in early postnatal ontogenesis. The rats with the TNFalpha administered during their 3 weeks of life differed from the control those by a change in the orienting behaviour and enhanced anxiety. The role of the anti-inflammatory cytokins in the brain during different stages of ontogenesis is discussed.

The effects of proinflammatory cytokines on the formation of behavior in early postnatal ontogenesis.

Studies were performed to investigate impairments to the formation of behavior arising as a result of increases in the proinflammatory cytokine interleukin-1beta in early postnatal ontogenesis. The cytokine was given at pyrogenic or subpyrogenic doses for one week (the first, second, or third week of life). Behavior was assessed at prepubertal age and in the adult state in the open field and elevated cross maze tests. The greatest changes were seen in adolescent rats given interleukin-1beta during the first or third weeks of life. Impairments were seen after administration of pyrogenic and subpyrogenic doses of cytokine and were identical in females and males. Changes consisted of partial substitution of acts, increases in motor activity and decreases in investigative activity. After sexual maturation, these behavioral impairments were no longer seen.

Effects of serotonin synthesis blockade on interleukin-1 beta action in the brain of rats.

The ability of the brain serotonergic system to mediate the effects of interleukin-1beta (IL-1beta) was investigated. Intracerebroventricular administration of IL-1beta induced a significant pyrogenic reaction, depression in social behaviour, loss of body weight and reduced food intake in rats. Pre-treatment with p-chlorphenylalanine, an inhibitor of serotonin synthesis, blocked the IL-1beta-induced decrease in food intake and loss of body weight, but failed to alter the temperature increase and the decrease in communicative activity.

[Interleukin-1beta and depressive states]. / Interleikin-1beta i depressivnye sostoianiia.

Administration of Interleukin-1 beta (IL-1 beta) in pyrogenic and subpyrogenic doses induced a depression of social and exploratory behaviour in rats. A reduction in locomotor activity only occurred with pyrogenic doses of the IL-1 beta. The low dose induced the reduction whereas the high dose the increase of anxiety in elevated plus maze. The opposite effects of two doses of IL-1 beta were observed also in a test with saccharine.

Intracerebroventricular administration of substance P increases dopamine content in the brain of 6-hydroxydopamine-lesioned rats.

The interactions existing between substance P- and dopamine-positive neurons, notably in the basal ganglia, suggest that substance P may have therapeutic use in treatment of Parkinson's disease characterized by impaired dopaminergic transmission. The effects of intracerebroventricularly administered substance P were tested on the levels of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex of 6-hydroxydopamine-lesioned rats. Intracerebroventricular injection of 6-hydroxydopamine decreased the levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the brain structures under investigation. Administration of substance P in low dose (0.35 nmol/kg) had no effect on the 6-hydroxydopamine-induced reduction of the dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid contents in the brain. However, treatment with substance P in higher dose (3.5 nmol/kg) increased the concentrations of dopamine and its metabolites in the striatum, nucleus accumbens and frontal cortex relative to saline-treated group. Additionally, 6-hydroxydopamine lesions significantly increased 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum and nucleus accumbens. Substance P (3.5 nmol/kg) partially reversed lesion-induced increases in 3,4-dihydroxyphenylacetic acid/dopamine and homovanillic acid/dopamine ratios in the striatum, but did not alter these ratios in nucleus accumbens. To test whether substance P fragmentation is responsible for this phenomenon, substance P(5-11), which is one of the main substance P fragments in rat CNS, was administered in equimolar dose. Substance P(5-11) was found to have no effect on the content of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum and nucleus accumbens. In the frontal cortex, substance P(5-11) produced decreases in dopamine levels and increases in homovanillic acid/dopamine ratio. The results of this study suggest that substance P helps to restore dopamine deficit in the brain in an animal model of Parkinson's disease, with the positive effects being more prominent on the nigrostriatal than on the mesocorticolimbic dopaminergic system, but substance P(5-11) is not responsible for this effect.

[Cytokine neurobiology: behavior and adaptive responses]. / Neirobiologiia tsitokinov: povedenie i adaptivnye reaktsii.

Reactions of the brain to systemic LPS or IL-1 beta treatment were shown to have different thresholds, be mediated by different neurotransmitter systems, and have different mechanisms of realisation. Changes in behaviour and neurotransmitter systems activity of the hypothalamus induced by a systemic IL-1 beta treatment were shown to be mediated by its receptors in the brain. Expression of mRNA of the tumour necrosis factor was revealed in the rabbit brain following administration of high pyrogenic doses of the LPS. The data obtained corroborate the concept of the cytokines role in maintenance of the defence responses in activation of the immune system, as well as their probable role in normal mechanisms of physiological functions control.

[Conflict of motivations and the reaction of neutrophilic granulocytes in rats]. / Konflikt motivatsii i reaktsiia neitrofil'nykh granulotsitov u krys.

A motivational conflict induced a decrease in the cation proteins content in neutrophils within 12 hrs after the stress in make rats. Activity of enzymes taking part in the respiration did not change. A cyclic variation of the cation proteins content was found during the oestrus cycle in neutrophils of female rats.