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)

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

Immunogold electron microscopy was used to analyze and quantify the Glut1 glucose transporter in brain tissue from five patients undergoing surgery for treatment of seizures. Samples were prepared from two different regions of each resection: (1) the most actively spiking epileptogenic site, and (2) the least actively spiking region, as indicated by intraoperative EEG monitoring. Two configurations of endothelial cell Glut1 were observed. About one half of the capillary profiles examined displayed abundant Glut1 immunoreactivity on both luminal and abluminal endothelial membranes. In the remainder of the profiles, reduced Glut1 labeling was seen, but adjacent erythrocyte membranes remained highly Glut1 immunoreactive, suggesting that reduced endothelial Glut1 reactivity was not attributable to method artifacts. Immunogold studies using antisera to human glial fibrillary acidic protein and human serum albumin demonstrated increased quantities of these two epitopes in the extravascular regions in which more EEG spiking activity had been demonstrated. These observations were consistent with the hypotheses that capillary integrity was more compromised, and gliosis was quantitatively increased, in the more actively spiking region of the resection. Altered glucose transporter activity in the blood-brain barrier was characterized by a bimodal Glut1 distribution in which the smaller (type B) endothelial cells displayed low Glut1 immunoreactivity, whereas adjacent (and even contiguous) larger (type A) endothelial cells showed 5- to 10-fold greater expression of membrane Glut1 transporter protein. Because this transporter facilitates glucose entry to the brain, small pericapillary volumes of brain tissue may have quite different concentrations of glucose. We hypothesize that in complex partial seizures and other forms of brain insult, an alteration of blood-brain barrier Glut1 glucose transporter activity is indicated by the appearance of these two subpopulations of endothelial cells. In comparison with previous studies of human brain capillaries in hemangioblastoma and brain injury, endothelial Glut1 density was apparently reduced (interictally) in affected temporal lobes of patients with complex partial seizures.
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PMID:Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood-brain barrier. 942 3

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

Systemic creatine (Cr) supplementation increases brain phosphocreatine (PCr) and prevents hypoxic seizures in 15-day-old rabbits. Between 5 and 30 days of age during normal development, rabbit gray matter mitochondrial creatine kinase (Mi-CK) increases 400% while cytosolic CK (BB-CK) increases 60%. In white matter, both isoenzymes show smaller, similar increases (40%) during this period. The Cr transporter protein decreases 60% between 5 and 15 days in both regions. In vivo CK rate constants measured by (31)P nuclear magnetic resonance increase 30% between 10 and 20 days, and then fall 50% between 20 and 30 days in predominantly gray matter slices. Similar maturational changes are seen in predominantly white matter slices. Injecting Cr at 15 days does not significantly change BB-CK or Mi-CK isoenzymes or the in vivo CK reaction rate constants. Thus, the largest change in the CK system associated with suppression of hypoxic seizures in Cr-treated rabbits is increased PCr in gray and white matter.
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PMID:Brain creatine kinase and creatine transporter proteins in normal and creatine-treated rabbit pups. 1111 Nov 60

We report on the use of the voltage-gated calcium channel blocker (Vg-CCB), verapamil, as an add-on anticonvulsant medication in two girls, 4 and 14 years of age, who were affected by severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, a channelopathy caused by abnormalities in the voltage-gated sodium channel neuronal type alpha1 subunit (SCN1A) gene at 2q24. Both girls had pharmacoresistant epilepsy and developmental delay. Mutation analysis for the SCN1A gene revealed a missense mutation in exon 2 in the 4-year-old girl. Verapamil was co-administered in both children with a prompt response in controlling status epilepticus, myoclonic jerks, and partial and generalized seizures. The therapeutic effect lasted 13 months in the 14-year-old girl, while it is still present after a 20-month follow-up period in the 4-year-old girl who, in addition, has experienced improvement in motor and language development. The verapamil vVg-CCB, which crosses the blood-brain barrier (BBB): (a) inhibits the P-glycoprotein, an active efflux transporter protein expressed in normal tissue, including the brain, which is believed to contribute to the in situ phenomenon of multidrug resistance; and (b) may regulate membrane depolarization induced by abnormal sodium channels functions by modulating the abnormal Ca++ influxes into neurons with subsequent cell resting. This is the first report on long-lasting verapamil therapy in SMEI. The functional consequences of such in vivo modulating effects on Ca++ channels could contribute to rational targeting for future molecular therapeutic approaches in pharmacoresistant epileptic channelopathies.
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PMID:Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. 1948 7

Previous studies indicate that DBA/2 mice may be a useful model of human sudden unexpected death in epilepsy (SUDEP), since these mice exhibit generalized convulsive seizures followed by respiratory arrest (RA). Respiratory deficits, following generalized convulsive seizures, are observed prior to SUDEP in patients. RA that occurs in DBA/2 mice following sound-induced seizures can be prevented by treatments that activate serotonin (5-HT) receptors. 5-HT receptor subtypes in brainstem respiratory centers are important in regulating normal respiration. The present study compared the expression of 5-HT subtype receptor proteins in excised brainstem tissue, containing the rostral ventral medulla respiratory region in DBA/2 mice vs. seizure-resistant C57BL/6J mice, using Western blot analysis. The results indicate that expression of specific 5-HT(2C), 5-HT(3), and 5-HT(4) receptor proteins in the brainstem tissue of DBA/2 mice is significantly diminished, while expression of the 5-HT(2B) receptors is significantly enhanced as compared to C57BL/6J mice. No difference in expression of 5-HT transporter protein is seen. These findings suggest that the DBA/2 mice are susceptible to RA, in part, because of the altered expression of 5-HT receptors. Preliminary studies indicate that 5-HT(2C) receptors may be particularly important, since a 5-HT(2C) agonist is very effective in blocking RA in DBA/2 mice.
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PMID:Abnormal serotonin receptor expression in DBA/2 mice associated with susceptibility to sudden death due to respiratory arrest. 2001 91

Using pentylenetetrazol (PTZ) kindling, we collected hippocampal tissue from standard response and kindling resistant animals, measuring hippocampal mRNA with real-time PCR of glutamate transporters GLAST, GLT-1, and EAAC1 and the sodium-coupled neutral amino acid transporter (SNAT) 1, SNAT2, and SNAT3. In addition, we measured mRNA of glutamine synthetase (GS), phosphate-activated glutaminase (PAG), glutamic acid decarboxylase (GAD) 1, GAD2, and vesicular inhibitory amino acid transporter (VIAAT). Fully kindled animals had decreased expression of mRNA in the hippocampus for GLAST and GAD2 compared with saline injected control. mRNA for SNAT1, SNAT2, SNAT3, GS, and VIAAT was increased. After induction of generalized tonic-clonic seizures by PTZ there were no differences in mRNA at 24h after seizures, equaling baseline quantities except for GAD1, which was decreased. When levels were measured at 30days after a PTZ induced convulsive seizure, we found increased levels of GLT-1, SNAT1 and GS, but decreased levels of GAD1. When these animals, serving as control for the 30day interval between the last convulsive seizure in the kindled experimental group, were analyzed, we found that GLT-1, SNAT3, GAD1 and VIAAT differed in that GLT-1 was decreased and the others increased. Animals found resistant to kindling had strikingly different mRNA patterns, with markedly up-regulated mRNA of proteins that transport glutamate into neurons and glia; SNAT1 was up regulated as well. Up-regulation of genes in kindling resistant animals supports the hypothesis that clearance of glutamate, conversion to glutamine and transport of glutamine into neurons, has the effect of raising the threshold for convulsive seizures and attenuating kindling.
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PMID:Differential molecular regulation of glutamate in kindling resistant rats. 2113 36

The hereditary stomatocytoses are a series of dominantly inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glucose transporter 1 (glut1) deficiency syndromes (glut1DSs) result from mutations in SLC2A1, encoding glut1. Glut1 is the main glucose transporter in the mammalian blood-brain barrier, and glut1DSs are manifested by an array of neurologic symptoms. We have previously reported 2 cases of stomatin-deficient cryohydrocytosis (sdCHC), a rare form of stomatocytosis associated with a cold-induced cation leak, hemolytic anemia, and hepatosplenomegaly but also with cataracts, seizures, mental retardation, and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. On the basis of a 3-dimensional model of glut1, we propose potential mechanisms underlying the phenotypes of the 2 mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia, and sdCHC phenotypes are compared and discussed.
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PMID:Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. 2179 20

The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.
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PMID:The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. 2381 Aug 36

Glucose transporter protein type 1 deficiency syndrome is a metabolic disorder manifesting as cognitive impairment, acquired microcephaly, epilepsy, and/or movement disorder caused by mutations in the SLC2A1 gene. We describe a cohort of isolated and familial cases of glucose transporter protein type 1 deficiency syndrome, emphasizing seizure semiology, electroencephalographic (EEG) features, treatment response and mutation pathogenicity. SLC2A1 mutations were detected in 3 sporadic and 4 familial cases. In addition, mutations were identified in 9 clinically unaffected family members in 2 families. The phenotypic spectrum of glucose transporter protein type 1 deficiency is wider than previously recognized, with considerable intra-familial variation. Diagnosis requires either hypoglycorrachia followed by SLC2A1 sequencing or direct gene sequencing. A ketogenic diet should be the first line of treatment, but more flexible diets, like the Atkins modified diet, can also be followed. Carbonic anhydrase inhibitors, such as acetazolamide or zonisamide, can be effective for seizure control.
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PMID:The many faces of Glut1 deficiency syndrome. 2334 81


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