Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Expression of mRNA for glutamate-aspartate transporter (GLAST/GluT-1/EAAT1) was studied in the brain of the rat which presented recurrent limbic seizure following systemic administration of kainic acid (KA) by in situ hybridization and Northern blot analysis. The expression of GLAST mRNA was markedly increased after 12 h and peaked after 48 h in animals which demonstrated limbic seizure. The induction of the mRNA were observed in the small non-neuronal cells in the hippocampus, especially around CA3 region and hilus. In contrast, there was no change in GLAST mRNA levels in KA injected seizure-free animals. These findings suggest that GLAST mRNA is induced by seizure and increased extracellular glutamate levels during seizure may be important for induction of GLAST mRNA.
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PMID:Increased transcription of glutamate-aspartate transporter (GLAST/GluT-1) mRNA following kainic acid-induced limbic seizure. 964 60

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

The glutamatergic system has been shown to be important for the induction of epileptiform activity and the development of epileptogenesis. To investigate the role of the astroglial glutamate transporter GLAST in epileptogenesis, we examined amygdala (AM)-kindled and pentylenetetrazole (PTZ)-induced seizures in GLAST-deficient mice (GLAST(-/-)) and compared them to those observed in wild-type mice (GLAST(+/+)) and maternal C57Black6/J (C57) mice. AM-kindling resulted in no significant differences in afterdischarge threshold or in the seizure responses induced by first stimulation between these groups. In addition, although no significant differences were seen in kindled seizure development, the generalized seizure duration of AM-kindled seizures in GLAST(-/-) mice was significantly prolonged (approximately 35%) compared with that of C57 mice. Furthermore, GLAST(-/-) mice showed more severe stages of PTZ-induced seizures than GLAST(+/+) mice, and the latency to the onset of seizures was significantly shorter for the mutant mice. These results indicate that GLAST is one of factors determining seizure susceptibility.
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PMID:Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. 1052 47

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

Recent studies support a critical role for the glutamatergic system and glutamate transporters in the pathogenesis of epilepsy. The glial glutamate transporters GLT-1 (L-glutamate transporter) and GLAST (L-glutamate/L-aspartate transporter) are known to be responsible for the majority of glutamate reuptake from the synaptic cleft and constitute one mechanism by which extracellular glutamate levels may be controlled. The present study therefore compared GLT-1 and GLAST mRNA levels in the genetically absence epilepsy rat from Strasbourg (GAERS) with those of age-matched non-epileptic controls. The GAERS rat has been proposed as an animal model of inherited human absence epilepsy, displaying recurrent, generalised, non-convulsive seizures that originate from thalamic and cortical structures. In situ hybridisation with 35S-labelled oligonucleotide probes demonstrated substantial and significant increases in GLT-1 mRNA levels in the ventromedial nucleus of the thalamus (VM) and the subthalamic nucleus (STN) of GAERS rats. Increases in GLAST mRNA were found in the primary somatosensory cortex (SS1) and temporal cortex (Te) of GAERS. These data, along with previous studies, suggest that regional imbalances in GABAergic and glutamatergic systems may be associated with the pathogenesis of absence seizures in GAERS.
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PMID:Glial glutamate transporter mRNAs in the genetically absence epilepsy rat from Strasbourg. 1064 92

Severe head injury in humans causes recurrent seizures; this form of epilepsy appears to correlate with occurrence of parenchymal hemorrhage. Injection of ferric cations, one component of hemoglobin, into rat amygdala, causes lipid peroxidation, and recurrent spontaneous seizures. We wondered whether regulation of extracellular glutamate might be perturbed as a mechanism of chronic epileptogenesis, therefore levels of glutamate transporter proteins GLT-1, GLAST and EAAC-1 were measured in ipsilateral and contralateral hippocampi removed from rats having spontaneous iron-induced limbic seizures. The neuronal transporter EAAC-1 was elevated bilaterally up to 30 days following the microinjection that initiated seizures. The neuronal transporter EAAC-1 was elevated bilaterally up to 30 days following the microinjection that initiated seizures. The glial transporter GLT-1 increased 5 and 15 days after iron injection on the side contralateral to the injection then returned to basal levels 30 days after the lesion. GLAST also showed an initial increase but at 15 and 30 days after injection, when experimental animals were experiencing spontaneous limbic behavioral seizures, this protein was down-regulated. The results suggest that iron-induced epileptogenesis involves alteration in glial glutamate transport that may lead to enhanced excitation within the hippocampus.
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PMID:Sequential changes in glutamate transporter protein levels during Fe(3+)-induced epileptogenesis. 1077 Dec 46

We used northern and western blotting to measure the quantity of glutamate and GABA transporters mRNA and their proteins within the hippocampal tissue of rats with epileptogenesis. Chronic seizures were induced by amygdalar injection of kainic acid 60 days before death. We found that expression of the mRNA and protein of the glial glutamate transporters GLAST and GLT-1 were down-regulated in the kainic acid-administered group. In contrast, EAAC-1 and GAT-3 mRNA and their proteins were increased, while GAT-1 mRNA and protein were not changed. We performed in vivo microdialysis in the freely moving state. During the interictal state, the extracellular glutamate concentration was increased, whereas the GABA level was decreased in the kainic acid group. Following potassium-induced depolarization, glutamate overflow was higher and the recovery time to the basal release was prolonged in the kainic acid group relative to controls. Our data suggest that epileptogenesis in rats with kainic acid-induced chronic seizures is associated with the collapse of extracellular glutamate regulation caused by both molecular down-regulation and functional failure of glutamate transport.
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PMID:Collapse of extracellular glutamate regulation during epileptogenesis: down-regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid. 1115 61

Dysembryoplastic neuroepithelial tumour (DNT) is a rare low-grade, mixed neuronal and glial tumour, usually associated with pharmacologically intractable, complex partial or generalised seizures which date from childhood. The prognosis after surgery is favourable. We present a classic case of DNT occurring in an 18-year-old male, who presented simple partial seizures without signs of raised intracranial pressure. CT and MR demonstrated focal mass located in the right temporal lobe. Histologically there were found the features of a typical DNT architecture with mixed cellular composition. The response to surgery was excellent. The tumour has not recurred, and the control of seizures remained good. Immunostaining for glutamate receptor GluR-2 showed stronger immunopositivity in neurones dispersed within the tumour and especially in margins of lesion as compared with apparently normal cerebral cortex. The expression of both excitatoryamino acid transporterproteins EAAT1 and EAAT2 was weaker then in normal cortex and uneven. This perhaps may explain the mechanism of seizures (elevated glutaminergic stimulation), and may suggest the excitotoxic damage of neurones.
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PMID:Dysembryoplastic neuroepithelial tumour (DNT). Is the mechanism of seizures related to glutamate? An immunohistochemical study. 1168 Jun 32


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