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

The level of the mRNAs encoding the AMPA-selective glutamate receptors-A and -B, alternatively splice variants, Flip and Flop, was studied by in situ hybridization in the brains of rats kindled by Schaffer collateral/commissural-fiber stimulation. In comparison to control animals, the expression level of the Flip variant of both GluR-A and GluR-B mRNAs was bilaterally enhanced in the dentate granule neurons of kindled animals 24 h after last-generalized seizure, whereas no obvious alterations were observed in the GluR-A Flop and GluR-B Flop mRNA variants. In kindled animals, studied 1 month after the last seizure, GluR-A Flip and GluR-B Flip mRNA had returned to control levels. We suggest that these changes may result in an enhanced glutamate receptor sensitivity in the fascia dentata during kindling.
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PMID:Hippocampal kindling increases the expression of glutamate receptor-A Flip and -B Flip mRNA in dentate granule cells. 130 May 3

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
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PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78

Increasing evidence implicates glutamate receptor over-stimulation in the neurotoxicity associated with a host of metabolic insults, including seizures and hypoxia-ischemia. To begin to understand more completely the role of energy metabolism in the mechanism of neuron death following excitatory amino acid exposure, we investigated the effects of kainic acid exposure on metabolic rate in cultured hippocampal cells using a recently developed silicon microphysiometer. The device gives a continual real-time measure of metabolism in relatively small numbers of cells, as assessed by efflux of protons generated at least in part by ATP hydrolysis and lactic acid production. In the first half of this report, we characterize the feasibility of using this device for measuring cellular metabolism in hippocampal cultures. Metabolic rate in both astrocytes and neurons was readily detectable, with a high signal-to-noise ratio. The rate was proportional to the number of cells and was sensitive to metabolic enhancement or depression. We then utilized this device to study metabolic responses to the excitotoxin kainic acid. We observed a receptor-mediated, dose-dependent increase in metabolic rate upon stimulation by kainic acid, with an EC50 of approximately 100 microM. Exposure to toxic levels of kainic acid for 10 min produced an initial elevation (for 2 hr) in metabolic rate and then a gradual decline in metabolism over the next 8 hr that preceded a measurable loss of cell viability. This study further delineates a time window for the onset of kainic acid-induced damage. The results clearly show the feasibility of using silicon microphysiometry for assessing metabolism of brain cultures and for exploring the relationship between metabolism and synaptic activation.
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PMID:Effects of excitotoxin exposure on metabolic rate of primary hippocampal cultures: application of silicon microphysiometry to neurobiology. 154 39

Quantitative autoradiography was used to examine central binding sites for L-[3H]glutamate in amygdaloid-kindled rats since receptors for excitatory amino acids have been implicated in epileptiform activity and seizure behaviors. In tissue from rats killed five days after two kindled seizures, the ipsilateral hippocampus, entorhinal, perirhinal and parietal cortices had significantly (35-100%) greater densities of binding sites for L-[3H]glutamate than the opposite, contralateral side or operated, unstimulated controls. These regions receive excitatory inputs from the amygdala via the entorhinal cortex. Dissociation constants were not altered and significant differences were not observed in the binding parameters for L-[3H]glutamate between control and kindled rats or ipsilateral and contralateral sides of the amygdala, corpus striatum, nucleus accumbens or substantia nigra. The proportion and affinity of N-methyl-D-aspartate (NMDA)-sensitive binding sites for L-[3H]glutamate was unchanged after kindling, as were the relative proportions of kainate- and AMPA-(DL-alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid) sensitive sites. However, the density of NMDA and non-NMDA receptor subtypes was increased in the ipsilateral hippocampus, entorhinal, perirhinal and parietal cortices of kindled rats. These findings of specific, unilateral glutamate receptor up-regulation may indicate adaptive responses to the enhanced excitation found in kindling, and are consistent with other neuronal changes reported in early kindling.
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PMID:Unilateral up-regulation of glutamate receptors in limbic regions of amygdaloid-kindled rats. 168 Jul 40

Excessive activation of excitatory amino acid receptors has been implicated in the neuronal degeneration caused by ischemia, hypoglycemia, and prolonged seizures. We have observed directly the time course and regional vulnerability of hippocampal neurons to glutamate receptor-mediated injury in organotypic hippocampal cultures, a preparation which combines accessibility and long-term survival with preservation of regional differentiation and neuroanatomic organization. Cultures were incubated with the fluorescent dye propidium iodide which selectively enters and stains cells only after membrane damage. After 5 to 10 min of a 30-min exposure to kainate (100 microM), large neurons in the hilus of the dentate were first to become brightly fluorescent. Propidium staining subsequently appeared in the other regions of the hippocampus and increased to a maximum over the first 6 h of recovery. NMDA (10 microM) caused propidium staining that was limited to CA1 and the dentate gyrus of the cultures, sparing CA3, consistent with the regions of highest NMDA receptor density in vivo. Glutamate (1 mM) caused a delayed, progressive pattern of staining that began in CA1 (2 to 4 h after exposure), then extended to include CA3 and finally the dentate gyrus over the next 24 h. Release of LDH activity into the media was slower and less sensitive than propidium staining. Histologic degeneration was limited to neurons 24 h after agonist exposure and was consistent with the propidium staining. NMDA, kainate, and glutamate each produced a unique pattern of neuronal injury. Most notably, glutamate had low potency as a toxin and its pattern of neuronal injury was not reproduced by NMDA.
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PMID:Direct observation of the agonist-specific regional vulnerability to glutamate, NMDA, and kainate neurotoxicity in organotypic hippocampal cultures. 171 7

Domoate, a glutamate analog, is believed to be responsible for a seafood poisoning incident that caused acute neurological disturbances and chronic memory impairment in some victims, with the incidence of mortality and neuropsychological morbidity being highest among the aged. Domoate expresses neurotoxic (excitotoxic) activity in vitro by an action at the kainate subtype of glutamate receptor, and when administered to adult rats, it mimics kainate in causing status epilepticus and a severe seizure-brain damage syndrome. Because domoate is exceedingly expensive, we explored the feasibility of using kainate to study the age-linked features of domoate neurotoxicity. We administered kainate subcutaneously in various doses to young (5-6 months), middle-aged (12-13 months), and old (22-25 months) rats and found the middle-aged and old rats significantly more sensitive than young rats to the neurotoxic actions of kainate. Low doses of kainate, which were nontoxic to young rats, frequently triggered status epilepticus, associated brain damage, and precipitous death in old rats. Middle-aged rats were more sensitive than young rats, but less sensitive than old rats to kainate neurotoxicity. These results suggest that the kainate-treated rat may be a useful model for studying mechanisms underlying age-related aspects of the human domoate neurotoxic syndrome.
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PMID:Age-related sensitivity to kainate neurotoxicity. 174 99

Specific [3H]vinylidene kainic acid binding to the kainate-sensitive subtype of glutamate receptor was studied in brain of 31-day-old non-epileptic Sprague-Dawley control and two colonies of genetically epilepsy-prone rats using in vitro autoradiographic techniques. At 37.5 nM [3H]vinylidene kainic acid, specific [3H]vinylidene kainic acid binding was reduced significantly by 18 and 22% in dorsal and ventral hippocampal formation stratum lucidum of 31-day-old genetically epilepsy-prone-9 rats compared with non-epileptic controls. Hippocampal [3H]vinylidene kainic acid binding was reduced in genetically epilepsy-prone-3 rats by 15 and 18%, but these reductions were not statistically significant. Saturation of [3H]vinylidene kainic acid binding studies indicated that the total number of ventral hippocampal [3H]vinylidene kainic acid binding sites was decreased by 21% in genetically epilepsy-prone-3 rats and 28% in genetically epilepsy-prone-9 rats. The reduction in ventral hippocampal [3H]vinylidene kainic acid binding in genetically epilepsy-prone rats resembles the reduction in ventral hippocampal [3H]vinylidene kainic acid binding sites observed in perinatal hypothyroid rats. As genetically epilepsy-prone rats are hypothyroid during the neonatal period, the reduction in hippocampal [3H]vinylidene kainic acid binding in the genetically epilepsy-prone rats may be a consequence of a hypothyroid-induced defect in the development or maturation of the hippocampal mossy fiber projection in genetically epilepsy-prone rats. An alternative hypothesis is that the putative occurrence of spontaneous limbic seizures in genetically epilepsy-prone rats may lead secondarily to a reduction in hippocampal [3H]vinylidene kainic acid binding sites.
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PMID:Decrease in hippocampal [3H]vinylidene kainic acid binding in genetically epilepsy-prone rats. 216 44

Domoic acid (Dom), a rigid analog of the excitotoxic amino acids, glutamate and kainic acid, is believed to be the mussel neurotoxin responsible for a recent food poisoning incident in Canada that killed some people and left others with memory impairment. Since the literature contains very little information pertaining to Dom excitotoxicity, we have systematically evaluated the neuroexcitatory properties of Dom in vitro (cultured hippocampal neurons) and its neurotoxic properties both in vitro (chick embryo retina) and in vivo (adult rat). In the in vitro experiments, the properties of Dom were compared with those of kainic acid, N-methyl-D-aspartate (NMDA) and quisqualate, each of which is a prototypic agonist at a different subtype of glutamate receptor. Currents induced in hippocampal neurons by Dom and kainic acid were identical and displayed a linear current/voltage relationship (in contrast to NMDA currents) and were nondesensitizing (in contrast to quisqualate currents). Dom currents were not blocked by NMDA antagonists but were blocked by CNQX, an antagonist of non-NMDA receptors. In the chick embryo retina, Dom induced a lesion pattern having the same distinctive characteristics as a kainic acid lesion which differs from that induced by either NMDA or quisqualate, and the Dom lesion was blocked by CNQX but not by NMDA antagonists. Subcutaneous administration of Dom (2.5-3 mg/kg) to adult rats resulted in an acute seizure-brain damage syndrome almost identical to that induced in rats by KA (12 mg/kg) and having important features analogous to the neurotoxic syndrome observed in the human food poison victims.
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PMID:Domoic acid: a dementia-inducing excitotoxic food poison with kainic acid receptor specificity. 217 Jan 63

It has been suggested that endogenous chemical substances such as adenosine, released during a seizure attack, may act as anticonvulsants in vivo. To further investigate this putative role, we have tested adenosine and stable adenosine analogues for anticonvulsant activity in vitro against ictal-like epileptiform activity induced by the removal of magnesium ions from medium superfusing wedges and slices of rat neocortex. Purinoceptor agonists attenuated such burst activity with a potency profile of L-phenylisopropyl-adenosine greater than 2-chloroadenosine greater than adenosine, suggesting that their anticonvulsant actions were mediated via the A1 adenosine receptor sub-type. Adenosine exerted no apparent effect on responses to agonists acting at glutamate receptor sub-types, implying no direct postsynaptic activity at glutamatergic synapses. Adenosine receptor antagonists, the methylxanthines (3-isobutyl-1-methylxanthine greater than theophylline) markedly enhanced established epileptiform activity and reversed the anticonvulsant action of adenosine. The selectivity of this reversal was demonstrated by the lack of effect of methylxanthines on pentobarbitone-induced inhibitions of epileptiform bursts. When added to a normal medium containing 1 mM magnesium, the methylxanthines were unable to induce long-lasting ictal-like epileptiform activity.
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PMID:A1 adenosine receptor-mediated block of epileptiform activity induced in zero magnesium in rat neocortex in vitro. 246 56

Neurons dissociated from the hippocampal formations of neonatal rats were grown in medium containing kynurenic acid (a glutamate receptor antagonist) and elevated Mg2+. Such chronically blocked neurons, when first exposed to medium without blockers (after 0.5-5.0 months), generated intense seizure-like activity. This consisted of bursts of synchronous electrical responses that resembled paroxysmal depolarization shifts and sustained depolarizations that, in some neurons, nearly abolished the resting potential. Sustained depolarizations were usually reversed by timely application of kynurenate or 2-amino-5-phosphonovalerate, indicating that continuous activation of glutamate receptors was required for their maintenance. Prolonged periods of intense seizure-like activity usually killed most neurons in the culture. This system allows seizure-related cellular mechanisms to be studied in long-term cell culture.
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PMID:Seizure-like activity and cellular damage in rat hippocampal neurons in cell culture. 256 Mar 92


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