The hippocampus as the determinant structure generating epileptic activity during korazol kindling

It has been shown in chronic experiments on rats that two periods of EEG and behavioral alterations may be distinguished during korazol kindling. The bursts of slow waves and spike-wave activity appear on the EEG during the first period as response to subthreshold doses of korazol, which is accompanied behaviorally by standing and myoclonuses. The second period is characterized by the appearance of high-frequency polymorphous generalized seizure discharges on the EEG accompanied by clonicotonic seizures. Interictal and ictal epileptic discharges appear primarily in the hippocamp and then in other brain structures during the development of korazol kindling. The conclusion is made that the hippocamp plays the role of a pathological determinant structure in the development of chronic brain epileptization during korazol kindling.     

Effect of intrauterine exposure to ethanol on synthesis of various phospholipids in the rat brain during the postnatal period

Male rats, whose mothers were given ethanol during pregnancy, were injected inorganic P32 into lateral brain ventricles. Some animals during 1 hour before decapitation were subjected to stress. Phosphatidylethanolamine, phosphatidylcholine and phosphatidylserine were isolated from neocortex and hippocamp. Prenatal alcohol treatment led to 30% inorganic P32 incorporation increase into neocortex phosphatidylcholine. Stress was followed by phosphatidylcholine synthesis level decrease in neocortex by 13% and in hippocamp by 26%. Amplitude of phospholipid synthesis alterations increased after both prenatal alcohol treatment and stress. The results show that prenatal alcohol treatment results in essential disfunction of brain phospholipids synthesis.     

2 types of chronic epileptogenesis in rabbits during kindling stimulation of the hippocampus

The development of convulsant readiness in rabbits during kindling electrical stimulation of the hippocamp was studied as was the dependence of the motor seizure pattern on the degree of epileptiform activity generalization in the CNS. The kindling electrical stimulation of the hippocamp gave rise to the formation in different rabbits of the two main types of afterdischarges. One of them was characterized by high-frequency and high-amplitude spikes (total duration 8-30 s) and the other one by continuous, rather long (50-100 s) hypersynchronous paroxysms. In the interictal period, the animals with the first type demonstrated the occurrence of spontaneous spikes (in all the brain structures under study) that sometimes progressed to a more or less prolonged seizure discharges. At the same time in the animals with the second type of afterdischarges the EEG in the interictal period was slightly different from normal. Despite this fact the seizures induced by electrical stimulation ran a milder course (short-term clonic seizures) in animals with the first type of afterdischarges as compared to those with the second type (long-term clonicotonic seizures). It is assumed that the severity of the motor seizure does not depend on the degree of epileptic activity generalization in the CNS.     

Metformin Plus Caloric Restriction Show Anti-epileptic Effects Mediated by mTOR Pathway Inhibition

Caloric restriction (CR) has anti-epileptic effects in different animal models, at least partially due to inhibition of the mechanistic or mammalian target of rapamycin (mTOR) signaling pathway. Adenosine monophosphate-activated protein kinase (AMPK) inhibits mTOR cascade function if energy levels are low. Since hyper-activation of mTOR participates in epilepsy, its inhibition results in beneficial anti-convulsive effects. A way to attain this is to activate AMPK with metformin. The effects of metformin, alone or combined with CR, on the electrical kindling epilepsy model and the mTOR cascade in the hippocampus and the neocortex were studied. Combined metformin plus CR beneficially affected many kindling aspects, especially those relating to generalized convulsive seizures. Therefore, metformin plus CR could decrease measures of epileptic activity in patients with generalized convulsive seizures. Patients that are obese, overweight or that have metabolic syndrome in addition to having an epileptic disease are an ideal population for clinical trials to test the effectiveness of metformin plus CR.     

Limbico-reticular relations during formation of various motivation responses in rabbits subjected to ethanol administration

Chronic experiments on rabbits with electrodes implanted into different limbic-midbrain structures were made to study the effects of a single intravenous injection of ethanol (0.5 g/kg) on the background EEG during formation of food motivation and avoidance behavior from the criterion of the power of the main EEG rhythms. Intravenous injection of ethanol resulted in an increase in the power of beta-, alpha- and theta-rhythms in the frontal cortex, and in that of alpha- and theta-rhythms in the occipital area of the neocortex. New patterns of the powers of the main EEG rhythms recorded in animals exposed to ethanol during electric stimulation of the lateral and ventromedial hypothalamus, evoking food motivation and avoidance behavior, as well as during electrical stimulation of the dorsal hippocamp and mesencephalic reticular formation that correlate with changes in the functions of the study limbic-mesencephalic structures attest to profound ethanol-induced abnormalities of the central mechanisms of food motivation and avoidance behavior.     

5'-Nucleotidase and adenosine deaminase activity in the rat brain upon prolonged effect of low radiation doses

The effect of combined low radiation doses (0.2-50.8 cGy) on the 5'-nucleotidase and adenosine deaminase activities in the rat hypothalamus, hippocamp and cerebral cortex during 45, 120 and 365 days was examined. It has been shown that the changes in the 5'-nucleotidase activity of the hypothalamus and hippocamp have a phase character. The direction of the changes in enzyme activity of the hypothalamus and hippocamp adenosine forming was dependent on the zone stay period and had the exactly opposite character depending on the early and prolonged stay period in the zone. 5'-nucleotidase activity was changed under the influence of mean and lesser doses with an increase of the zone stay period. No changes in the 5'-nucleotidase activity of the cerebral cortex were noted. No changes in the hypothalamic adenosine deaminase activity of rats that stayed in a zone during 45 days were revealed; under the effect of mean dose during 120 days the activity decreased and also in case of a higher dosage during one year. The adenosine deaminase activity in animal hippocamp decreased in rats only under the influence of the lesser dose, for 45-day period. The decrease in adenosine deaminase activity of the cerebral cortex that was noted under the effect of all the three doses during 45 days, the higher and mean doses during 120 days disappeared in a year.     

Kindling of the limbic structures with a shortened interstimulus interval

We investigated the possibility to produce hippocampal or amygdala kindling syndrome in rabbits which had been electrically stimulated at a fixed interval between stimuli at 5 min. Animals were prepared with chronically implanted electrodes (neocortex, hippocampus, amygdala, nucleus caudatus). The initial stimuli produced only localized effect, but repeated applications of the stimuli progressively increased the seizure activity resulting in generalized kindled convulsions after 2-4 h period. At the first stage generalized seizures were followed by long lasting refractory period, but at the end of the procedure almost all stimuli evoke major motor seizures and recurrent widely spread electrographic epileptic changes. The most noteworthy findings emerging from this study is the inhibition of postictal seizure inhibition period. This effect was independent of whether stimulated the electrode was positioned in the hippocampus or amygdala, but the hippocampal formation occupied the central position for the once and propagation of the seizure activity in all cases. When established this syndrome persisted without any attenuation for some weeks. It was concluded that this model of rapid development of kindling syndrome is useful for investigation of the nature of epilepsy and postictal seizure inhibition.     

Amygdala Kindling Potentiates Seizure-Stimulated Immediate-Early Gene Expression in Rat Cerebral Cortex

Kindling induces long-term adaptations in neuronal function that lead to a decreased threshold for induction of seizures. In the present study, the influence of amygdala kindling on levels of mRNA for the immediate-early genes (IEGs) c-fos, c-jun, and NGF1-A were examined both before and after an acute electroconvulsive seizure (ECS). Although amygdala kindling did not significantly influence resting levels of c-fos mRNA in cerebral cortex, ECS-stimulated levels of c-fos mRNA (examined 45 min after ECS) were approximately twofold greater in the cerebral cortex of kindled rats relative to sham-treated controls. The influence of kindling on IEG expression was dependent on the time course of kindling, as ECS-stimulated levels of c-fos mRNA were not significantly increased in stage 2 kindled animals. ECS-stimulated levels of c-jun and NGF1-A mRNA were also significantly increased in cerebral cortex of kindled rats relative to sham-treated controls. The influence of kindling on IEG expression was long-lasting because an acute ECS stimulus significantly elevated levels of c-fos and c-jun mRNA in the cerebral cortex of animals that were kindled 5 months previously. In contrast to these effects in cerebral cortex, kindling did not influence ECS-stimulated levels of c-fos mRNA in hippocampus. Finally, immunohistochemical studies revealed lamina-specific changes in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of the anxiolytic agent buspirone with serotonin and other synaptic receptors in the human brain

Buspirone and Mj 138-05 (up to 0.1 mM) did not displace specifically bound (3H) tryptamine, (3H) strychnine, (3H) flunitrazepam and (3H) imipramine in human cortical and hippocampal membrane preparations. At the same time both compounds displayed similar to serotonin affinity (IC50 in the range of 2-6 microM) for (125I)-LSD specific binding sites in the human cortex and hippocamp. IC50 of serotonin and buspirone and Mj 138-05 for (3H) LSD (2 nM) specific binding sites in the hippocamp was determined as 0.14 microM, 2.3 microM and 6.1 microM, respectively; and for (3H) serotonin specific binding sites in the hippocamp as 0.005 microM, 3.8 microM and 21 microM, respectively. The affinity for human cortex (3H) LSD binding sites was 10-fold lower in case of serotonin and 4-fold lower in case of buspirone and Mj 138-05 than in the hippocamp. However, the affinity for (3H) serotonin binding sites in the cortex was the same as in the hippocamp in case of serotonin and 12-15-fold lower than in the hippocamp in case of buspirone and Mj 138-05. It is concluded that in human brain buspirone and Mj 138-05 interact with micromolar affinity with 5 HT2 and are capable of binding to a subpopulation of 5 HT1 receptors in the hippocamp.     

Long-term changes in EEG spectra of the hippocampus and neocortex during pharmacological action on the cholinergic system

Statistical analysis of EEG spectra averaged over 10-min periods showed that inhibitor of acetylcholinesterase physostigmine induced the long-term (tens of minutes) characteristic changes in the electric activity of the dorsal hippocampus (CA1 field) and somatosensory cortex of unrestrained rats. With increasing the physostigmine dose from 0.05 to 0.5 or 1 mg/kg the averaged power of the theta-rhythm did not rise in the range of 3.6-4.9 Hz and was suppressed in the range of 5.7-11.9 Hz both in the hippocampus and neocortex. The maximal frequency shifted to the left (from 3.6-6.4 to 3.6-4.9 Hz). In contrast to this, the averaged power in the delta (1-1.5 Hz)-I and beta-2 ranges (20.3-26.5 Hz) significantly nonlinearly increased and that of the beta-1 substantially decreased. Scopolamine eliminated all extrema of the hippocampal and neocortical EEG spectra induced by physostigmine, which is indicative of the role of M-cholinoreceptors in these effects. The increased dose of physostigmine (1 mg/kg) produced inversion of the ratio between the averaged power of beta-2 in neocortex and hippocampus: it became significantly higher than in the neocortex. All these data suggest that the mechanisms of cholinergic modulation of the theta- and beta-rhythms are essentially different. We think that significant enhancement of the content of endogenous acetylcholine content produce a long-term tonic decay of the functional activity of the hippocampus and neocortex and play an important role in the mechanisms of dissociated states of memory and consciousness, contextual learning and conditioned switching.     

Effect of antihypoxic agents on the cyclic nucleotide content in different brain structures in normo-oxia and hypoxia

A study was made of the effects of isothiobarbamine and guthimine (10 and 50 mg/kg, respectively) on the content of cAMP and cGMP in the brain cortex (BC) and hippocamp under normal conditions and hypoxia. Isothiobarbamine did not change the content of both cyclic nucleotides under normoxia, whereas under hypoxia it reduced the level of the cyclic nucleotides in the BC and raised it in the hippocamp. Guthimine increased their content in the BC and did not change it in the hippocamp under normoxia, whereas under hypoxia it increased the cAMP content in the hippocamp and did not change it in the BC. The cGMP content descended in both the structures under study.     

Quantitative analysis of the mosaic formation of neurons of the neocortex and hippocampus of the mouse

Computer analysis of the maps of distribution of intensively labelled neurons (ILN) in the frontal sections of area 6 of the frontal neocortex and area CA 1 of the dorsal hippocamp was performed in 1-day-old mice who received a single injection of 3H-thymidine on the 13th-17th day of embryogenesis (E 13-E 17). It has been revealed that ILN are distributed in rather close, vertically oriented groups. In mice exposed to isotope in E 14-E 16, the average number of ILN in a group was 4.44 +/- 0.25 for area 6 and 4.35 +/- 0.16 for area CA 1. The data available have confirmed an earlier postulated hypothesis on the discrete arrangement of neurogenesis loci in the ventricular zone of the embryonic brain. Additional calculations have allowed to conclude that in E 14-E 16 period the locus of the ventricular neocortex during one mitotic cycle produces 7-9 cells starting the neuronal differentiation, while during the whole period of neurogenesis in the neocortex the column consisting of 84-108 neurons is formed, which is close to the number of neurons in a minicolumn of the neocortex (110 cells).     

Spectral analysis of the effects of nomifensine on bioelectric activity of the rat brain]

The influence of nomifensine on bioelectrical activity of sensorimotor cortex, dorsal hippocamp and lateral hypothalamus in conscious rats in free behavior was studied. The pharmacological and EEG analysis of nomifensine action on EEG power spectra by Fourier technique was measured. It was established that nomifensine evoked an increase and stabilization of the dominant peak in EEG spectra in the left and right cortex and in the left hippocamp, while in the other ranges of frequency a decrease was observed. The effects on hypothalamus was opposite--EEG power spectra decreased in all the ranges. The authors conclude that nomifensine evokes higher level of wakefulness, vigilance of the animals. This is likely to underlie neurophysiological mechanisms of optimal behavior due to stimulants of CNS, including nomifensine.     

Synaptic degeneration and remodelling after fast kindling of the olfactory bulb

Kindling of the olfactory bulb using a novel fast protocol (within 24 h) was studied in rats. In target brain regions, the effects of kindling were measured on the concentration of glial fibrillary acidic protein (GFAP) by dot-blot and on the concentrations of neural cell adhesion molecule (NCAM) and the 25 kDa synaptosomal associated protein of the D3 immunoprecipitate (D3(SNAP-25)) by crossed immunoelectrophoresis. Bilateral increases in the levels of GFAP, indicating activation of astrocytes, were detected in primary olfactory cortical projection areas, including the piriform cortex, and also in the basolateral amygdala and dentate gyrus, suggesting that these regions may be functionally altered during the kindling process. In the piriform cortex and dentate gyrus increased NCAM/D3(SNAP-25) ratios found ipsilaterally at seven days after kindling probably reflect an elevated rate of synaptic remodelling. At this time, however, an overall pattern of ipsilateral decreases in the synaptic marker proteins NCAM and D3(SNAP-25) indicated that this remodelling occurred on a background of synaptic degeneration. These results confirm previous studies showing that kindling is associated with synaptic remodelling and neuronal degeneration in the hippocampal formation and extends the area of plasticity to include the piriform cortex which is believed to be central to the kindling process.     

3H-1-glutamate binding with the synaptic membranes isolated from the cerebral cortex and hippocampus of Krushinski?-Molodkina strain rats

Specific binding of 3H-L-glutamate to synaptic membranes isolated from the cerebral cortex and hippocamp of Wistar and Krushinsky-Molodkina (KM) rats examined both in a quiet awake state and after audiogenic seizures was compared. The dissociation constant (KD) values and binding capacity (Bmax) for KM rats did not differ significantly from the corresponding parameters of binding determined for Wistar rats (KD--89.8 +/- 18.1 and 102.6 +/- 12.5 nm, Bmax--1.23 +/- +/- 0.08 and 1.30 +/- 0.15 pmol/mg for the cortex and hippocamp, respectively). After audiogenic seizures the binding capacity of the hippocamp of KM rats was reduced by 30%. It is suggested that hippocampal glutamate receptors of KM rats are involved in the mechanism of convulsive activity formation.     

Influence of lithium hydroxybutyrate on the electroencephalographic effects of fenamin

Lithium hydroxybutyrate (10 mg/kg) prevents the amphetamine-induced EEG arousal and amplitude frequency alterations in the motor and visual cortex, posterior hypothalamus, midbrain reticular formation, and caudate nucleus but potentiates the action of the psychostimulant on the EEG of the hippocamp and amygdala. The response to the light flickering rhythm in the visual cortex remains within initial upon concurrent administration of both the drugs.     

Effects of destruction and activation of limbic structures on formation of convulsive and emotional disorders during picrotoxin kindling

In the experiments on rats it was shown that the picrotoxin kindling, which consists of the progressive increasing of convulsive reactions during daily systemic administration of picrotoxin in subconvulsive dosages results also in the development of the pathologically enhanced defensive reactions. The destruction of hippocampal structures by kainic acid prevented the seizure syndrome, while their activation due to blood injection in hippocampus promoted its development; under these conditions the kindling of pathologically enhanced defensive reactions was not significantly changed. Bilateral amygdalar destruction significantly attenuated the development of pathologically increased defensive behavior; under these conditions the seizure syndrome was not significantly changed. The data are discussed on the theory of generator, and systemic mechanisms of neuropathologic syndromes and show that picrotoxin kindling results in the formation of two different pathologic systems which cause the development of two mentioned syndromes: seizure syndrome and syndrome of pathologically enhanced defensive behavior.     

Hematologic and various immunologic parameters of the body response in experimental epileptogenesis

The aim of present study was to reveal the figures that show the organism reactivity at various stages of the amygdala kindling. We found that a completed kindling formed by stimulation of the piriform cortex, is accompanied by systemic changes in white and red blood. First stages of kindling during the cortical nucleus stimulation are characterised by reactive changes of erythrocytes and thrombocytes suggesting that changes occur in the homeostasis. We discuss possible mechanisms of these changes.     

Bicuculline-induced blockade of neocortical rapid kindling suggesting facilitative GABAergic action on seizure development

Summary To investigate how GABAergic function affects seizure development, the effects of a GABA antagonist, bicuculline, on neocortical and hippocampal kindling were examined in chronically prepared rabbits. Kindling-inducing stimulations consisted of stimulus trains repeated at 5-min interstimulus intervals to produce so-called rapid kindling. The changes in after-discharge (AD) durations induced by each of 15 trials of stimulus trains per session were compared before and 30 min after i.p. injection of bicuculline solution (2 mg/kg) in each of three kindling groups consisting of 5 rabbits each, i.e. visual cortical, motor cortical and hippocampal kindling groups. In the visual cortex and to a less extent, the motor cortex kindling groups, the AD durations were shortened after bicuculline injection and did not show the progressive prolongation seen before the injection. In contrast, the hippocampal kindling group showed a further marked prolongation of the AD durations after the injection. The bicuculline-induced blockade of neocortical kindling suggests facilitative GABAergic action on seizure development, while the drug-induced enhancement of hippocampal kindling reflects the known inhibitory GABAergic action.     

Hippocampal Kindling in the Rat Is Associated with Time-Dependent Increases in the Concentration of Glial Fibrillary Acidic Protein

The effect of hippocampal kindling on the regional brain concentration of total glial fibrillary acidic protein (GFAP), a marker of reactive astrocytes, was studied in partially kindled rats, and in fully kindled rats after a post-kindling period of 24 h, 1 week, and 2 months. GFAP concentration was measured in arbitrary units by dot-blots. In the hippocampus, dentate gyrus, basolateral amygdala, pyriform cortex, and entorhinal cortex, limbic structures which are known to be involved in the kindling process, there was an increase in GFAP concentration which was maximal in the fully kindled animals studied after 24 h. In most brain areas, GFAP concentration was still elevated 1 week post-kindling, but had declined to control level 2 months post-kindling. A significant increase in GFAP was also found in septum, ventral pallidum/accumbens nucleus, and primary motor cortex of kindled rats with a post-kindling period of 24 h, whereas in several other brain regions GFAP was unchanged. These results suggest that astrocyte activation, indicative of degenerative changes in nearby neurons, is a transient and regional phenomenon in kindling occurring only during the development of the kindled state.