UMLS:C0036572 - FACTA Search

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

Glutamate and aspartate are excitatory neurotransmitters that have been implicated in a number of pathological states of the nervous system. Accumulation of extracellular excitatory amino acids can be cytotoxic and may also lower the seizure threshold in epilepsy. An important function of the Na(+)-dependent high-affinity excitatory amino acid transporter (EAAT) is the reuptake of secreted amino acid neurotransmitter, possibly maintaining extracellular amino acid concentrations at nontoxic and nonepileptogenic levels. We have isolated the mouse cDNA for EAAT2, a neurotransmitter transporter that shares extensive amino acid sequence homology with one of several previously cloned high-affinity glutamate transporters. The mouse EAAT2 amino acid sequence shares 99 and 97% identity with its rat and human homologues, respectively. It is expressed predominantly in the brain, where it may function as a glia-specific transporter. In an interspecific backcross analysis Eaat2 maps to the central region of mouse chromosome 2, where it is located near quantitative trait loci that modulate neuroexcitability and seizure frequency in mouse models of alcohol withdrawal and epilepsy.
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PMID:Mouse excitatory amino acid transporter EAAT2: isolation, characterization, and proximity to neuroexcitability loci on mouse chromosome 2. 769 42

There is increasing evidence that levels of glutamate are elevated in certain brain regions immediately prior to and during induction and propagation of seizures. Modulation of high-affinity glutamate uptake is a potential mechanism responsible for the elevated levels observed with Seizures. To date, three distinct Na(+)-dependent glutamate transporters have been cloned from rat and rabbit: GLT-1, GLAST, and EAAC-1. We performed a series of experiments to determine whether levels of these transporters are altered in amygdala-kindled rats. Levels of GLT-1, GLAST, and EAAC-1 were examined in three brain regions (hippocampus, piriform cortex/amygdala, and limbic forebrain) by quantitative immunoblotting using subtype-specific antibodies. GLAST protein was down-regulated in the piriform cortex/amygdala region of kindled rats as early as 24 h after one stage 3 seizure and persisting through multiple stage 5 seizures. In contrast, kindling induced an increase in EAAC-1 levels in piriform cortex/amygdala and hippocampus once the animals had reached the stage 5 level. NO changes in GLT-1 were observed in any region examined. Changes in transporter levels could contribute to the changes in glutamate levels seen with kindling.
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PMID:Alterations in glutamate transporter protein levels in kindling-induced epilepsy. 908 27

In situ hybridization techniques and quantitative western blotting were used to study the expression of the glial glutamate transporter GLT-1 and GLAST in the brains of normal (implanted, non-kindled) and fully kindled rats. Wistar rats were implanted with stimulating electrodes in the basolateral amygdala, and killed 28 days after the stimulated group had shown stage 5 seizures on five occasions. The brains were processed for in situ hybridization of messenger RNA for GLT-1 using 35S-labelled oligonucleotide probes or digoxigenin-labelled riboprobes. Paired (kindled and non-kindled) sections were used for qualitative and quantitative analyses. Image analysis of autoradiograms showed no change in expression of GLT-1 messenger RNA in any region of the hippocampus or in the cortex. An increase in expression of GLT-1 messenger RNA (expressed as percentage difference of control) was observed bilaterally in the striatum in kindled animals (16-21%, P<0.05). Nuclear emulsion-dipped sections showed predominant glial cell labelling in the hippocampus. Particle density analysis revealed reduced cell labelling in some kindled vs control pairs but overall there was no significant reduction in labelling in CA1. Equivalent results were found in CA1 using digoxigenin-labelled riboprobes. Quantitative immunoblotting also revealed no change in GLT-1 or GLAST transporter protein in the hippocampus of kindled animals. From these data we conclude that the enduring seizure susceptibility associated with the fully kindled state is unlikely to involve alterations in hippocampal GLT-1 messenger RNA or GLT-1 and GLAST transporter protein expression.
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PMID:Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats. 914 92

Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.
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PMID:Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. 918 80

The genetically epilepsy-prone rat is an animal model of inherited generalised tonic-clonic epilepsy that shows abnormal susceptibility to audiogenic seizures and a lowered threshold to a variety of seizure-inducing stimuli. Recent studies suggest a crucial role for glutamate and GABA transporters in epileptogenesis and seizure propagation. The present study examines the levels of expression of the messenger RNAs encoding the glial and neuronal glutamate transporters, GLT-1 and EAAC-1, and the neuronal GABA transporter, GAT-1, in paired male genetically epileptic-prone rats and Sprague Dawley control rats using the technique of in situ hybridization. In a parallel study, semiquantitative immunoblotting was used to assess GLT-1 and EAAC-1 protein levels in similarly paired animals. Animals were assessed for susceptibility to audiogenic seizures on six occasions, and killed seven days following the last audiogenic stimulus exposure. Rat brains were processed for in situ hybridization with radioactive 35S-labelled oligonucleotide probes (EAAC-1 and GAT-1), 35S-labelled riboprobes (GLT-1), and Fluorescein-labelled riboprobes (GLT-1 and GAT-1) or processed for immunoblotting using subtype-specific antibodies for GLT-1 and EAAC-1. Semiquantitative analyses were carried out on X-ray film autoradiograms in several brain regions for both in situ hybridization and immunoblotting studies. Reductions in GAT-1 messenger RNA were found in genetically epileptic-prone rats in all brain regions examined (-8 to -24% compared to control). Similar reductions in GLT-1 messenger RNA expression levels were seen in cortex, striatum, and CA1 (-8 to -12%) of genetically epileptic-prone rats; the largest reduction observed was in the inferior colliculus (-20%). There was a tendency for a reduced expression of EAAC-1 messenger RNA in most regions of the genetically epileptic-prone rat brain although this reached statistical significance only in the striatum (-12%). In contrast, no significant differences in GLT-1 and EAAC-1 protein between genetically epileptic-prone rats and control animals were observed in any region examined, although there was a tendency to follow the changes seen with the corresponding messenger RNAs. These results show differences in the messenger RNA expression levels of three crucial amino acid transporters. For the two glutamate transporters, GLT-1 and EAAC-1, differences in messenger RNA levels are not reflected or are only partially reflected in the expression of the corresponding proteins.
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PMID:Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat. 968 60

The expression of excitatory amino acid transporters (EAATs) in rat hippocampus was studied following kainic acid-induced seizure activity in vivo and in hippocampal slice cultures. Protein and mRNA levels of the glial (EAAT2) and neuronal (EAAT3) transporters were determined with affinity-purified antibodies and oligonucleotide probes, respectively. Kainate treatment decreased EAAT3 immunoreactivity in stratum lacunosum moleculare within 4 h of seizure onset. Upon pyramidal cell death (5 days after kainate treatment), EAAT3 immunoreactivity in stratum pyramidale of CA1 and in stratum lacunosum moleculare was almost completely eliminated. The rapid effect of kainate on EAAT3 expression was confirmed by in situ hybridization; EAAT3 mRNA levels were decreased in CA1 and CA3 regions within 4-8 h of seizure onset. Kainate treatment had an opposite effect on levels and expression of EAAT2. Developmental studies indicated that the rapid regulation of transporter expression was not observed in rats younger than 21 days, an observation congruent with previous reports regarding the resistance of young rats to kainate. In hippocampal organotypic cultures, which lack a major excitatory input from the entorhinal cortex, kainate produced a slow decrease in [3H]d-aspartate uptake. This study indicates that an early effect of kainate treatment consists of down-regulation of the neuronal transporter EAAT3 in restricted hippocampal regions, together with a modest increase in the expression of the glial transporter EAAT2. Differential regulation of neuronal and glial glutamate transporters may thus play a role in kainate-induced seizure, neurotoxicity and neuronal plasticity.
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PMID:Changes in expression of neuronal and glial glutamate transporters in rat hippocampus following kainate-induced seizure activity. 1003 13

Glutamate is the major excitatory neurotransmitter in the central nervous system and is implicated in the pathogenesis of neurodegenerative diseases. Five human glutamate transporters have been cloned and are responsible for the removal of potentially excitotoxic excess glutamate from the extracellular space. In this study we consider whether there are selective changes in the expression of the glutamate transporters in the medial temporal cortex and hippocampus from temporal lobe epilepsy patients, which might contribute to the development or maintenance of seizures. Since disruption of the glial transporter excitatory amino acid transporter 2 in mice results in lethal spontaneous seizures, we were interested primarily in studying changes in this transporter. Using in situ hybridization we show that there was no reduction in the level of excitatory amino acid transporter 2 encoding messenger RNA in the temporal lobe epilepsy cases compared to post mortem controls and indeed there was a relative increase in content of excitatory amino acid transporter 2 messenger RNA per cell in temporal lobe epilepsy cases. Western blotting showed that there was no change in the excitatory amino acid transporter 2 protein content in temporal lobe epilepsy cases as compared to post mortem controls. A small reduction in the level of the second astroglial transporter protein, excitatory amino acid transporter 1, was observed in temporal lobe epilepsy cases. Surprisingly, immunohistochemical experiments using a polyclonal antiexcitatory amino acid transporter 2 antibody, showed a different localization of this protein in epilepsy derived tissue as compared to post mortem controls although glial markers such as glial fibrillary acidic protein and glutamine synthase showed similar patterns of staining. However, repeating this experiment using control tissue from non-temporal lobe epilepsy biopsies demonstrated that this change in the excitatory amino acid transporter 2 transporter localization occurred post mortem. These data suggest that major changes in the level of expression of the glutamate transporters do not play an important role in the development of human temporal lobe epilepsy but may be implicated the aetiology of other types of epilepsy.
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PMID:Expression of the glutamate transporters in human temporal lobe epilepsy. 1033 23

Glutamate, the principal excitatory neurotransmitter in the brain, acts on three families of ionotropic receptor--AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid), kainate and NMDA (N-methyl-D-aspartate) receptors and three families of metabotropic receptor (Group I: mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7 and mGlu8). Glutamate is removed from the synaptic cleft and the extracellular space by Na+-dependent transporters (GLAST/EAAT1, GLT/EAAT2, EAAC/EAAT3, EAAT4, EAAT5). In rodents, genetic manipulations relating to the expression or function of glutamate receptor proteins can induce epilepsy syndromes or raise seizure threshold. Decreased expression of glutamate transporters (EAAC knockdown, GLT knockout) can lead to seizures. In acquired epilepsy syndromes, a wide variety of changes in receptors and transporters have been described. Electrically-induced kindling in the rat is associated with functional potentiation of NMDA receptor-mediated responses at various limbic sites. Group I metabotropic responses are enhanced in the amygdala. To date, no genetic epilepsy in man has been identified in which the primary genetic defect involves glutamate receptors or transporters. Changes are found in some acquired syndromes, including enhanced NMDA receptor responses in dentate granule cells in patients with hippocampal sclerosis.
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PMID:Glutamate receptors and transporters in genetic and acquired models of epilepsy. 1051 65

Elevated levels of extracellular glutamate ([Glu](o)) can induce seizures and cause excitotoxic neuronal cell death. This is normally prevented by astrocytic glutamate uptake. Neoplastic transformation of human astrocytes causes malignant gliomas, which are often associated with seizures and neuronal necrosis. Here, we show that Na(+)-dependent glutamate uptake in glioma cell lines derived from human tumors (STTG-1, D-54MG, D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is up to 100-fold lower than in astrocytes. Immunohistochemistry and subcellular fractionation show very low expression levels of the astrocytic glutamate transporter GLT-1 but normal expression levels of another glial glutamate transporter, GLAST. However, in glioma cells, essentially all GLAST protein was found in cell nuclei rather than the plasma membrane. Similarly, brain tissues from glioblastoma patients also display reduction of GLT-1 and mislocalization of GLAST. In glioma cell lines, over 50% of glutamate transport was Na(+)-independent and mediated by a cystine-glutamate exchanger (system x(c)(-)). Extracellular L-cystine dose-dependently induced glutamate release from glioma cells. Glutamate release was enhanced by extracellular glutamine and inhibited by (S)-4-carboxyphenylglycine, which blocked cystine-glutamate exchange. These data suggest that the unusual release of glutamate from glioma cells is caused by reduction-mislocalization of Na(+)-dependent glutamate transporters in conjunction with upregulation of cystine-glutamate exchange. The resulting glutamate release from glioma cells may contribute to tumor-associated necrosis and possibly to seizures in peritumoral brain tissue.
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PMID:Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. 1059 60

Hepatic encephalopathy (HE) and portal-systemic encephalopathy (PSE) are the terms used interchangeably to describe a complex neuropsychiatric syndrome associated with acute or chronic hepatocellular failure, increased portal systemic shunting of blood, or both. Hepatic encephalopathy complicating acute liver failure is referred to as fulminant hepatic failure (FHF). The clinical manifestations of HE or PSE range from minimal changes in personality and motor activity, to overt deterioration of intellectual function, decreased consciousness and coma, and appear to reflect primarily a variable imbalance between excitatory and inhibitory neurotransmission. Pathogenic mechanisms that may be responsible for HE have been extensively investigated using animal models of HE, or cultures of CNS cells treated with neuroactive substances that have been implicated in HE. Of the many compounds that accumulate in the circulation as a consequence of impaired liver function, ammonia is considered to play an important role in the onset of HE. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent overactivation of the ionotropic Glu receptors, mainly the N-methyl-D-aspartate (NMDA) receptors. Hepatic encephalopathy complicating chronic liver failure appears to be associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a net increase of inhibitory neurotransmission, as a consequence of at least two factors. The first is down-regulation of Glu receptors resulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. Liver failure inactivates the Glu transporter GLT-1 in astrocytes. The second factor is an increase in inhibitory neurotransmission by gamma-aminobutyric acid (GABA) due to (a) increased brain levels of natural benzodiazepines; (b) increased availability of GABA at GABA-A receptors, due to enhanced synaptic release of the amino acid; (c) direct interaction of modestly increased levels of ammonia with the GABA-A-benzodiazepine receptor complex; and (d) ammonia-induced up-regulation of astrocytic peripheral benzodiazepine receptors (PBZR). Brain ammonia is metabolised in astrocytes to glutamine (Gln), an osmolyte, and increased Gln accumulation in these cells may contribute to cytotoxic brain edema, which often complicates FHF. Glutamine efflux from the brain is an event that facilitates plasma-to-brain transport of aromatic amino acids. Tryptophan and tyrosine are direct precursors of the aminergic inhibitory neurotransmitters, serotonin and dopamine, respectively. Changes in serotonin and dopamine and their receptors may contribute to some of the motor manifestations of HE. Finally, oxindole, a recently discovered tryptophan metabolite with strong sedative and hypotensive properties, has been shown to accumulate in cirrhotic patients and animal models of HE.
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PMID:Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. 1061 92

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