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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To find general principles in the cellular mechanisms of epileptogenesis, one must analyze experimental epilepsy models and determine what exists in common between them. We consider here afterdischarges in hippocampal slices induced using either (1) GABAA blockade (e.g. with bicuculline), (2) a bathing solution lacking Mg2+ ions (low Mg-induced epilepsy), or (3) 4-aminopyridine (4AP). By 'afterdischarge' we mean an event that lasts hundreds of milliseconds or more, involving the synchronous firing of all the neurons in a population, shaped into a long initial burst and a series of one or more secondary bursts, and terminating in a prolonged afterhyperpolarization (AHP). We propose that the following features exists in common between these three experimental epilepsies: (1) recurrent excitatory synaptic connections; (2) sustained dendritic synaptic excitation, mediated by either AMPA or NMDA receptors, or both; (3) an intrinsic cellular response to sustained excitation, consisting of rhythmical dendritic bursts, primarily mediated by Ca spikes. In conclusion, if the picture outlined here proves correct, then the stereotypic appearance of epileptic afterdischarges--consisting of synchronized population bursts in series, whatever the network alteration leading to seizures--does indeed reflect a common set of mechanisms. The mechanisms cannot, apparently, be formulated in simple terms of this receptor or that receptor. Rather, we suggest, the recurrent excitatory synapses are able, under diverse circumstances, collectively to produce sustained dendritic conductances in neuronal populations. Pyramidal neurons, by virtue of their normal intrinsic membrane properties, respond to such sustained conductances with rhythmical bursts. The recurrent synapses, in a dual role, serve to maintain the synchrony of these bursts, and so shape the activity into a synchronized oscillation.
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PMID:Are there unifying principles underlying the generation of epileptic afterdischarges in vitro? 780 Aug 28

Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-D-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg(2+)-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8-10 min) but not late (> 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments.
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PMID:Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices. 784 1

We studied some of the physiological and pharmacological properties of an in vitro model of epileptic seizures induced by elevation of [K+]0 (to 8 mM and 10 mM) in combination with lowering of [Mg2+]0 (to 1.4 mM and 1.6 mM) and [Ca2+]0 (to 0.7 mM and 1 mM) in rat hippocampal slices. These concentrations correspond to the ionic constitution of the extracellular microenvironment during seizures in vivo. The resulting activity was rather variable in appearance. In area CA3 recurrent discharges were observed which resulted in seizure-like events with either clonic-like or tonic-clonic-like ictaform events in area CA1. With ion-sensitive electrodes, we measured the field potential and the changes in extracellular ion concentrations which accompany this activity. The recurrent discharges in area CA3 were accompanied by small fluctuations in [K+]0 and [Ca2+]0. The grouped clonic-like discharges in area CA1 were associated with moderate increases in [K+]0 and small decreases in [Ca2+]0 in the order of 2 mM and 0.2 mM, respectively. Large, negative field-potential shifts and increases in [K+]0 to 13 mM, as well as decreases in [Ca2+]0 by up to 0.4 mM, accompanied the tonic phase of ictaform events. The ictaform events were not blocked by D-2-aminophosphonovalerate (2-APV) but were sensitive to 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) alone and in combination with 2-APV and ketamine. In order to determine the pharmacological characteristics of the ictaform events we bath-applied most clinically employed anticonvulsants (carbamazepine, phenytoin, valproate, phenobarbital, ethosuximide, trimethadione) and some experimental anticonvulsants (losigamone, vinpocetine, and apovincaminic acid). Carbamazepine, phenytoin, valproate, and phenobarbital were effective at clinically relevant doses. The data suggest that the high-K+ model of epileptiform activity is a good model of focal convulsant activity.
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PMID:Pharmacological and electrographic properties of epileptiform activity induced by elevated K+ and lowered Ca2+ and Mg2+ concentration in rat hippocampal slices. 790 41

Organic calcium channel blockers have been demonstrated to abolish epileptic activity in various experimental models. Furthermore, it was shown that the antiepileptic efficacy of the organic calcium channel blocker verapamil was significantly augmented when the KCl concentration background was elevated to levels normally occurring during epileptic seizures. The aim of the present investigation was to test whether flunarizine, which in contrast to verapamil is able to penetrate the blood brain barrier, suppresses epileptic activity in neocortical slice preparations, and whether this effect would be enhanced by raising the KCl background concentration. Epileptic activity was induced in neocortical slices of guinea pigs by omission of Mg2+ from the superfusate. As a measure of epileptic activity, field potentials were recorded from layers III and V. They appeared within approx 30 min after omission of Mg2+ from the bath solutions. The frequency of occurrence in normal and elevated KCl concentration was 47 +/- 10/5 min and 46 +/- 9/5 min, respectively. Flunarizine, in concentrations of 3.2 and 18 mumol/l, abolished epileptiform activity dose dependently. A 90% depression occurred within 194 +/- 27 and 376 +/- 27 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. Elevating the KCl back-ground concentration to 8 mmol/l significantly enhanced the antiepileptic efficacy of flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. The experiments demonstrate that flunarizine suppresses epileptic activity in neocortical preparations, with enhanced action in elevated K+ levels.
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PMID:Flunarizine shows increased antiepileptic efficacy with elevated K+ levels in low magnesium induced epileptic activity (neocortical slices, guinea pig). 793 95

The Mongolian gerbil displays spontaneous seizures and is used as a model for global ischemia. This study investigated the electrophysiological events associated with 0-Mg(2+)-induced seizures in gerbil hippocampal slices. In the rat hippocampal slice, 0-Mg2+ medium leads to rapid extracellular epileptic depolarization (ED) accompanied by long-term synaptic failure. Both evoked and spontaneous epileptiform activity was observed in the gerbil hippocampal slice after the introduction of the 0-Mg2+ aCSF. However, unlike the rat, ED was rarely observed in the gerbil hippocampal slice (2/17). When ED occurred, synaptic responses recovered (75%) within 20 min. This resistance to epileptic depolarization did not generalize to experimental ischemia-induced depolarization. Anoxia in 2 mM D-glucose produced anoxic depolarization in all gerbil hippocampal slices tested (6/6).
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PMID:Resistance to epileptic, but not anoxic, depolarization in the gerbil hippocampal slice preparation. 802 97

Tissue samples from the caudate nucleus were obtained from eight children (eight to 172 months of age) who underwent hemispherectomies for the relief of intractable seizures. Neurophysiological, pharmacological and morphological properties of caudate neurons were characterized by intracellular recordings in an in vitro slice preparation. These properties were compared with those of tissue obtained from animal studies. Electrophysiological properties of human caudate neurons that were similar to those of cat caudate and rat neostriatal cells included resting membrane potential, input resistance, action potential rise time, fall time, duration and action potential afterhyperpolarization amplitude, as well as the general characteristics of locally evoked synaptic responses. Properties that were different included action potential amplitudes and time-constants. Human caudate neurons also displayed responses similar to those of cat caudate or rat neostriatal cells to manipulation of excitatory amino acid receptor systems and to dopamine application. Kynurenic acid, a broad-spectrum excitatory amino acid receptor antagonist, decreased the amplitude of evoked synaptic responses, indicating that they were partially mediated by excitatory amino acids. In Mg2+ free Ringer's solution, the amplitudes and durations of postsynaptic responses were increased and bursts of action potentials were induced. These effects were mediated by activation of N-methyl-D-aspartate receptors since they were blocked by 2-amino-5-phosphonovalerate, a specific N-methyl-D-aspartate-receptor antagonist. Iontophoretic application of N-methyl-D-aspartate also induced membrane oscillations and bursts in almost all caudate neurons. Dopamine decreased the amplitude of postsynaptic responses, an effect antagonized by domperidone, a selective D2 dopamine receptor antagonist. Developmentally, the greatest change was an increase in action potential amplitude, although input resistance decreased and action potential afterhyperpolarization amplitude increased. Postsynaptic responses were similar across age. All but one of the caudate neurons identified by intracellular injection of biocytin or Lucifer Yellow were medium-sized spiny cells. These experiments show that human caudate neurons display a number of electrophysiological properties similar to rat neostriatal or cat caudate neurons recorded in brain slices. Furthermore, few electrophysiological parameters changed significantly over the age period examined suggesting that the human caudate at eight months displays many of the neuronal functions of the more mature caudate nucleus.
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PMID:Neurophysiological, pharmacological and morphological properties of human caudate neurons recorded in vitro. 819 Feb 75

Maternal and fetal magnesium homeostasis is reviewed. Current evidence suggests that pregnancy-associated growth is unlikely to cause maternal magnesium deficiency and that the case for magnesium supplementation during pregnancy is unproven. Similarly, data do not support the use of magnesium in prevention of preterm labor or its preferential use in tocolysis. Magnesium might have a role to play in the prevention/treatment of eclamptic seizures. Hypomagnesaemia occurs in poorly controlled diabetic pregnancy and may be part of the cause of the hypomagnesaemia in the infants of such mothers. Fetal magnesium homeostasis is poorly understood as is the mechanism of placental transfer. Data from the rat suggest that the bulk of maternofetal placental magnesium transfer occurs via a transcellular route utilising a Na+/Mg2+ exchanger and that maternofetal flux of magnesium is reduced in the presence of maternal diabetes mellitus. Further study of diabetic pregnancy will increase our understanding of magnesium homeostasis both in normal and abnormal pregnancy.
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PMID:Magnesium and pregnancy. 826 17

In the present study the water and ion (Na+, K+, Ca2+, Fe3+, Se4+, Mg2+, Mn2+, Mn2, Se4+, Cu2+) content in the brain of genetically epilepsy-prone rats (GEPRs) and of 21-, 45-, and 60-day-old DBA/2 mice were determined, and compared with those measured in normal controls (Sprague-Dawley rats and Swiss mice), to verify whether the predisposition to audiogenic seizures (AGS) may be partially related to changes in the cerebral osmotic and ionic state. Our findings clearly evidenziate two points: a) a more complex shift in brain ionic balance (rather than a peculiar modification in the concentration of a single ion) seems very likely involved in AGS susceptibility; (b) brain Ca2+ and Se4+ amounts, together with the water content, appear to be really important factors to which a role in abnormal seizure predisposition may be attributed.
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PMID:Genetically epilepsy-prone rodents show some changes of ion levels in the brain. 827 21

Intracellular recordings of layer V neurons from rat neocortical slices were obtained to examine the effects of reducing extracellular magnesium on inhibition. Magnesium-free solutions induced interictal and ictal-like events in cortical neurons. Changes in synaptic events underlying epileptogenesis were studied when extracellular calcium was raised (from 2 to 3-7 mM) since this delayed seizure activity. With increasing time of exposure of cells to magnesium-free solutions, there was a significant increase in the size and duration of both the depolarizing and slow synaptic hyperpolarizing responses, but the fast synaptic hyperpolarization significantly declined in amplitude. When cells were recorded with cesium acetate-filled microelectrodes slow hyperpolarizing responses were blocked, but depolarization of cells to 0 mV allowed an isolated fast hyperpolarizing response to be recorded following synaptic stimulation. The amplitude of this response was unchanged after exposure to magnesium-free solutions. Synaptic responses of cells initially bathed in an N-methyl-D-aspartate (NMDA) antagonist (CPP) were unchanged by subsequent exposure to magnesium-free solutions. CPP exposure by itself caused a decrease in depolarization duration, increase in fast hyperpolarizing amplitude, and decrease in slow hyperpolarization amplitude and duration. When the fast hyperpolarization was viewed in isolation (cesium recording electrodes) at 0 mV, the amplitude of this event was unchanged by exposure to CPP. Given these results stimulus-response characteristics of neocortical neurons were reassessed under control conditions. With higher intensity stimuli larger depolarizing and slow hyperpolarizing responses were evoked, but the fast hyperpolarization showed a decremental response. These effects were reversed when CPP was added. When NMDA activity was enhanced by exposure to magnesium-free solutions or electrical stimulation, the amplitude of excitatory events and slow hyperpolarizations increased, but fast inhibitory responses showed limited capacity for incremental recruitment. This suggests fast inhibition is saturated (maximal) at submaximal levels of excitation, and can be overcome by increasing levels of excitation. Such a process is active under physiological conditions, altering the efficacy of inhibition.
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PMID:Recruitment of inhibition by enhanced activation of synaptic NMDA responses in the rat cerebral cortex. 829 76

Effects of the cyclic AMP agonists 8-(4-chlorophenylthio)-adenosine 3':5' cyclic monophosphate (CPT-cAMP), dibutyryl cyclic AMP (dbcAMP) and forskolin were studied on extracellular field potentials in rat neocortex slices in vitro. CPT-cAMP and forskolin produced a prolonged enhancement of epileptiform activity resulting from removal of Mg2+ from the bathing medium. DbcAMP had no apparent effect except at high concentrations (1 mM), when it reduced bursting activity. Field potentials observed following electrical stimulation of the corpus callosum in the presence of Mg2+ were enhanced by CPT-cAMP and dbcAMP; however forskolin was without effect. Intracellular recording techniques demonstrated a transient excitatory influence of dbcAMP. The results indicate a role for cyclic AMP in seizure mechanisms.
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PMID:Cyclic AMP analogues increase excitability and enhance epileptiform activity in rat neocortex in vitro. 839 51


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