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)

The purpose of the present study was to examine the effects of GABA-producing cell transplants on audiogenic seizures (AGS). The M213-2O cell line was derived from fetal rat striatum and has GABAergic properties. This cell line was further modified to express human GAD(67) and produce elevated levels of GABA. The present study compares the effects of parent M213-2O cell transplants with those of GAD(67)-modified M213-2O cells in AGS-prone Long-Evans rats. Two weeks following implantation of engineered cells, latency to AGS-typical wild running was increased compared to nonimplanted subjects. Survival of the transplanted cells was confirmed by immunochemical labeling of GAD(67) and Epstein-Barr virus nuclear antigen. These findings support the use of GABA-producing cell lines to modify seizure activity.
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PMID:Transplantation of M213-2O cells with enhanced GAD67 expression into the inferior colliculus alters audiogenic seizures. 1242 37

To identify the roles of pyridoxal kinase (PLK) in epileptogenesis and the recovery mechanisms in spontaneous seizure, a chronological and comparative analysis of PLK expression in the gerbil hippocampus was conducted. PLK immunoreactivity in a pre-seizure group of seizure sensitive (SS) gerbils was more strongly detected than that in a seizure resistant (SR) group. The density of PLK immunoreactivity in a 30-min postictal group was significantly lower than that of a pre-seizure group. In a 12 h postictal group, PLK immunodensity recovered to pre-seizure level. The over-expression of PLK in the hippocampus of pre-seizure SS gerbils suggests that PLP play an important role in the modulation of GAD activity and GABA reuptake as mediated by membrane transporter via neurons.
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PMID:Changes in pyridoxal kinase immunoreactivity in the gerbil hippocampus following spontaneous seizure. 1244 66

1. Molecular mechanisms underlying increased hippocampal excitability in human temporal lobe epilepsy (TLE) are largely unknown. A disturbance of the imbalance between excitatory and inhibitory neurotransmission pathways in the epileptic hippocampus may contribute substantially to a decreased seizure threshold. 2. We have extended the investigation whether TLE is associated with changes in the expression of GAD67 and NMDAR1 by assessing the relative amounts of the mRNAs in human hippocampal samples by means of semiquantitative RT-PCR. The samples included 16 hippocampal slices obtained at surgery from intractable TLE (HS, n = 14; non-HS, n = 2) and 3 postmortem control hippocampi. 3. The ratio for the GAD/NMDAR1 transcripts was significantly higher in TLE cases when compared to the nonepileptic samples. Such findings are mainly a consequence of the increased amounts of GAD mRNA detected in the epileptic hippocampus. Compared with nonepileptic samples, and without correction for neuron losses, the amounts of NMDAR1 mRNA in HS are slightly reduced, and in the non-HS samples they are significantly increased, which is consistent with an increase of NMDAR1 in the hippocampal remaining neurons, as previously reported. 4. Our results also contribute to the indication of GAD67 mRNA upregulation in human TLE. A possible functional implication for the increased GAD mRNA levels could be a mechanism to reduce neuronal hyperexcitability, synchronization, and/or the spread of seizure.
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PMID:Glutamate NMDA receptor subunit R1 and GAD mRNA expression in human temporal lobe epilepsy. 1258 88

In the pilocarpine model of chronic limbic seizures, vulnerability of GABAergic interneurons to excitotoxic damage has been reported in the hippocampal CA1 region. However, little is known about the specific types of interneurons that degenerate in this region. In order to characterize these interneurons, we performed quantitative analyses of the different populations of GABAergic neurons labeled for their peptide or calcium-binding protein content. Our data demonstrate that the decrease in the number of GAD mRNA-containing neurons in the stratum oriens of CA1 in pilocarpine-treated rats involved two subpopulations of GABAergic interneurons: interneurons labeled for somatostatin only (O-LM and bistratified cells) and interneurons labeled for parvalbumin only (basket and axo-axonic cells). Stratum oriens interneurons labeled for somatostatin/calbindin or somatostatin/parvalbumin were preserved. The decrease in number of somatostatin- and parvalbumin-containing neurons was observed as early as 72 hours after the sustained seizures induced by pilocarpine injection. Many degenerating cell bodies in the stratum oriens and degenerating axon terminals in the stratum lacunosum-moleculare were observed at 1 and 2 weeks after injection. In addition, the synaptic coverage of the axon initial segment of CA1 pyramidal cells was significantly decreased in pilocarpine-treated animals. These results indicate that the loss of somatostatin-containing neurons corresponds preferentially to the degeneration of interneurons with an axon projecting to stratum lacunosum-moleculare (O-LM cells) and suggest that the death of these neurons is mainly responsible for the deficit of dendritic inhibition reported in this region. We demonstrate that the loss of parvalbumin-containing neurons corresponds to the death of axo-axonic cells, suggesting that perisomatic inhibition and mechanisms controlling action potential generation are also impaired in this model.
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PMID:Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine-induced seizures. 1268 7

Rasmussen's disease is an inflammatory, chronic and progressive brain disorder that usually presents with neocortical focal seizures resistant to conventional treatment and culminates in severe deterioration with hemiparesis, cognitive decline and aphasia. Viral infections and antibodies to the GluR3 receptor have been implicated in the physiopathology of this illness and T-cell mediation may play a role in the cerebral inflammatory process. Classical treatment consists of hemispherectomy of various magnitudes depending on cerebral involvement. The association between therapy-resistant epilepsy and autoimmune phenomena due to antibodies against glutamic acid decarboxylase (anti-GAD) have very recently begun to be studied. The discovery of this association led to a new focus and alternative therapies with immunosuppressors, immunoglobulins, steroids and plasmapheresis, alone or in combination, have begun to be tested with variable success. We describe a boy who was diagnosed in the early stages of Rasmussen's syndrome. He tested positive for anti-GAD antibodies and received treatment with immunoglobulins and steroids. After treatment the boy tested negative for anti-GAD antibodies and he remains asymptomatic after ten months.
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PMID:[Rasmussen's syndrome, an autoimmune disease]. 1498 28

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.
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PMID:Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. 1462 Aug 76

gamma-Aminobutyric acid (GABA)-mediated neurotransmission from the granule cells to CA3 is transiently expressed during the first 3 weeks of age in the rat. In the adult, seizures provoke this inhibitory signaling to reappear. To gain insight into the origin of GABA in these cells, we explored the expression of both isoforms of glutamic acid decarboxylase (GAD, 65 and 67 kDa), during development and after seizures in the adult rat. We found that GAD(67), but not GAD(65), is expressed in the mossy fibers of developing rats. In adults, GAD(67) is no longer detectable, unless seizures are induced. By contrast, GAD(65) is neither expressed in granule cells nor in their mossy fibers at any age nor after seizures, despite the presence of GAD(65) mRNA, confirmed by reverse transcription-polymerase chain reaction in situ.
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PMID:Glutamic acid decarboxylase (GAD)67, but not GAD65, is constitutively expressed during development and transiently overexpressed by activity in the granule cells of the rat. 1464 40

The present study was performed to determine whether the effects induced by GABA(B) receptor-acting drugs would be related with the alteration in GABA(B) receptor expression in the hippocampus using Mongolian gerbil, a genetic epilepsy model. The distribution patterns of both GABA(B) receptor 1A/B and GABA(B)receptor 2 immunoreactivities were similarly detected in the hippocampi of normal and seizure-prone gerbils. Following baclofen (GABA(B) receptor agonist) or phaclofen (GABA(B) receptor antagonist) treatment, GABA(B) receptor immunoreactivities were decreased or increased by dose-dependent manners, respectively. Vigabatrin (GABA transaminase inhibitor) or 3-mercaptopropionic acid (GAD inhibitor) treatment did not affect GABA(B) receptor expressions. These findings suggest that GABA(B) receptor expression in the gerbil hippocampus may be altered by baclofen or phaclofen treatment.
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PMID:Altered GABAB receptor immunoreactivity in the gerbil hippocampus induced by baclofen and phaclofen, not seizure activity. 1523 66

The dentate gyrus is believed to play an important pathophysiological role during experimentally induced kindling. In this study, we investigated whether an altered content of the calcium binding protein calbindin-D(28k) or an increased intrinsic excitability of hippocampal granule cells contribute to the induction of the kindling phenomenon. We determined the firing pattern of granule cells in hippocampal slices using perforated patch-clamp recordings in current clamp mode. The expression of calbindin-D(28k) and glutamic acid decarboxylase (GAD(67)) by granule cells was analyzed immunohistochemically. Rats developed secondarily generalized limbic seizures within approximately 11 days of twice-daily stimulation of the amygdala. As reported for other kindling paradigms, this protocol induced a clear up-regulation of GAD(67) in granule cells, indicating their involvement in the induced neuronal activity. However, when comparing kindled and control rats, we could not detect any differences in intrinsic excitability: Firing frequency, after-hyperpolarisations, action potentials, input resistance and membrane potentials were nearly identical between both groups. Furthermore, we did not observe any differences in the calbindin-D(28k) immunoreactivity between groups. In every slice, virtually all granule cells were found to be strongly calbindin-D(28k) positive, and there was no apparent reduction in the general level of calbindin-D(28k) expression. We conclude that changes in intrinsic membrane properties or in the calbindin-D(28k) content of granule cells are not necessary for the development of amygdala kindling.
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PMID:Calbindin-D28k content and firing pattern of hippocampal granule cells in amygdala-kindled rats: a perforated patch-clamp study. 1568 Sep 50

Diazepam (DZ) and phenobarbital (PH) are commonly used to treat early-life seizures and act on GABAA receptors (GABAR). The developing GABAergic system is highly plastic, and the long-term effects of postnatal treatment with these drugs on the GABAergic system has not been extensively examined. In the present study, we investigated the effects of prolonged DZ and PH treatment during postnatal development and then discontinuation on expression of a variety of genes involved in GABAergic neurotransmission during adulthood. Rat pups were treated with DZ, PH or vehicle from postnatal day (P) 10-P40 and then the dose was tapered for 2 weeks and terminated at P55. Expression of GABAR subunits, GABAB receptor subunits, GABA transporters (GAT) and GABA synthesizing enzymes (glutamic acid decarboxylase: GAD) mRNAs in hippocampal dentate granule neurons (DGNs) were analyzed using antisense RNA amplification at P90. Protein levels for the alpha1 subunit of GABAR, GAD67, GAT1 and 3 were also assessed using Western blotting. At P90, mRNA expression for GAT-1, 3, 4, GABAR subunits alpha4, alpha6, beta3, delta and theta and GABAB receptor subunit R1 was increased and mRNA expression for GAD65, GAD67 and GABAR subunits alpha1 and alpha3 were decreased in DGNs of rats treated with DZ and PH. The current data suggest that prolonged DZ and PH treatment during postnatal development causes permanent alterations in the expression of hippocampal GABA receptor subunits, GATs and GAD long after therapy has ended.
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PMID:Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. 1580 92


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