Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Kainate (KA) is a potent neuroexcitatory agent that induces seizure and brain damage syndromes with increasing efficiency during maturation. It has been suggested that the selective neuronal damage induced by KA may result not only from its depolarizing actions, but also from intracellular accumulation of Ca2+. The effects of KA are mediated by specific high-affinity receptors, enriched in the hippocampus. Members of this class of receptors, GluR5 and GluR6, have been characterized by cDNA cloning. Ca2+ permeability of the GluR6 receptor is determined by editing in the corresponding RNA. We report here a rapid PCR-based approach to assess in all experimental conditions the levels of GluR5 and GluR6 editing in the transmembrane TMII region. We show that editing in both GluR5 and GluR6 RNA is developmentally regulated and that different regions of the adult rat hippocampus demonstrate distinct levels of GluR6 editing.
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PMID:Assessing the extent of RNA editing in the TMII regions of GluR5 and GluR6 kainate receptors during rat brain development. 751 22

In adult rats, intraperitoneal administration of kainic acid, a glutamic acid analog and potent neurotoxin, induces persistent seizure activity that results in electrographic alterations and neuropathology that closely resemble human temporal lobe epilepsy. We used in situ hybridization to identify regions of altered glutamate and GABAA receptor gene expression following kainate-induced status epilepticus. In the CA3/CA4 area, the hippocampal region most vulnerable to neurodegeneration after kainate acid treatment, expression of GluR2 (the AMPA/kainate receptor subunit that limits Ca2+ permeability) and GluR3 was decreased markedly at 12 and 24 hr, times preceding neurodegeneration. These findings raise the possibility that increased formation of Ca(2+)-permeable AMPA/kainate receptors in the CA3/CA4 area may enhance glutamate pathogenicity. Expression of the GABAA alpha 1, subunit was also reduced, indicating a possible decrease in inhibitory transmission, which would also enhance excitotoxicity. GluR1 and NR1 expression was not significantly changed. In the dentate gyrus, a region resistant to neurodegeneration, concomitant increases in GluR2 and GluR3 expression were observed; GluR1, NR1, and GABAA alpha 1 mRNAs were not detectably altered. Analysis of emulsion-dipped sections revealed that the changes in GluR2, GluR3, and GABAA alpha 1 expression represented changes in mRNA content per neuron and were specific to pyramidal cells of the CA3/CA4 area and to granule cells of the dentate gyrus. These findings indicate that kainate seizures modify hippocampal glutamate and GABAA receptor expression in a cell-specific manner. Timing of the changes in glutamate and GABAA receptor mRNAs indicates that these changes may play a causal role in hippocampal neuronal cell loss following kainate-induced seizures.
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PMID:Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study. 818 36

An assessment of glutamate receptor subunit profiles was made in hippocampus and temporal lobe cortex of patients with refractory epilepsy. Molecular biological analyses using reverse transcription reaction (RT) followed by polymerase chain reaction (PCR) revealed changes in the distribution profile of the transcripts of AMPA/KA glutamate receptor subunits in hippocampal and cortical tissue from patients with refractory epilepsy when compared to similar tissue from six human and four non-human primate samples with no history of seizures or seizure medication. A severe mean decrease (38% of control) in mRNA for the GluR1 subunit was found in 400 mm cross-sections of hippocampus from patients with epilepsy. Less severe but significant reductions in that GluR1 subunit expression (54% of control) were exhibited in samples of excised temporal pole cortex from the same subjects. Message for the GluR4 subunit was also significantly decreased in hippocampus (68% of control), but in contrast to GluR1, GluR4 mRNA level was not decreased in temporal cortex. Levels of GluR2 mRNA were not significantly changed in epileptic hippocampal and cortical tissue relative to control samples. Protein levels of the GluR1 and GluR4 subunits quantified by Western blot analysis were also reduced in hippocampal and cortical tissue from epilepsy patients. Two other kainate subunit transcripts, GluR6 and KA1 also showed significant changes compared to non-epileptic tissue (136% and 71% of control, respectively). Results are discussed in terms of possible mechanisms by which protracted seizures could produce selective loss of certain AMPA/KA subunits.
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PMID:Changes in glutamate receptor subunit composition in hippocampus and cortex in patients with refractory epilepsy. 945 76

L-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors because in many experimental situations it is not possible to distinguish them from AMPA receptors. Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate. We have now generated mutant mice lacking the kainate-receptor subunit GluR6. The hippocampal neurons in the CA3 region of these mutant mice are much less sensitive to kainate. In addition, a postsynaptic kainate current evoked in CA3 neurons by a train of stimulation of the mossy fibre system is absent in the mutant. We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus. Our results indicate that kainate receptors containing the GluR6 subunit are important in synaptic transmission as well as in the epileptogenic effects of kainate.
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PMID:Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. 958 Feb 60

The editing status of mRNA at the Q/R site of the glutamate receptor subunits GluR2 and GluR6 modulates channel conductivity and ion selectivity of ionotropic AMPA/KA receptors. Alteration of the editing process may be involved in the debilitating effects of epilepsy. The ratio of unedited/edited (Q/R) forms of GluR2 and GluR6 subunits was examined in conjunction with the expression of two double-stranded RNA-specific adenosine deaminases (DRADA) in surgically excised hippocampus from patients with refractory epilepsy compared with that of control samples. In the majority of patients with long histories of epilepsy, the GluR2 transcript was detected in the completely edited form, however, in two (out of 16 tested) hippocampal samples of young subjects (2 and 10 years old) we were able to identify the unedited transcript of GluR2 subunit. The proportion of unedited fraction of GluR6(Q) subunit was decreased to 9% compared to control human hippocampus. We conclude that the editing process in epileptic specimens is selectively affected by seizure activity in the epileptic focus.
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PMID:Editing status at the Q/R site of the GluR2 and GluR6 glutamate receptor subunits in the surgically excised hippocampus of patients with refractory epilepsy. 969 3

This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.
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PMID:Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients. 984 88

Kainate (KA) is a potent neuroexcitatory agent in several areas of the adult brain, with convulsant and excitotoxic properties that increase as ontogeny proceeds. Besides its depolarizing actions, KA may enhance intracellular accumulation of Ca2+ to promote selective neuronal damage. The effects of KA are mediated by specific receptors recently considered to be involved in fast neurotransmission and that can be activated synaptically. KA receptors, e.g. GluR5 and GluR6 have been characterized by molecular cloning. Structure-function relationships indicate that in the MII domain of these KA receptors, a glutamine (Q) or arginine (R) residue determines ion selectivity. The arginine stems from post-transcriptional editing of the GluR5 and GluR6 pre-RNAs, and the unedited and edited versions of GluR6 elicit distinct Ca2+ permeability. Using a PCR-based approach, we show that in vivo, Q/R editing in the GluR5 and GluR6 mRNAs is modulated during ontogeny and differs substantially in a variety of nervous tissues. GluR5 editing is highest in peripheral nervous tissue, e.g. the dorsal root ganglia, where GluR6 expression is barely detectable. In contrast, GluR6 editing is maximal in forebrain and cerebellar structures where GluR5 editing is lower. Intra-amygdaloid injections of KA provide a model of temporal lobe epilepsy, and we show that following seizures, the extent of GluR5 and GluR6 editing is altered in the hippocampus. However, in vitro, high levels of glutamate and potassium-induced depolarizations have no effect on GluR5 and GluR6 Q/R editing. GluR6 editing is rapidly enhanced to maximal levels in primary cultures of cerebellar granule neurons but not in cultured hippocampal pyramidal neurons. Finally, we show that cultured glial cells express partially edited GluR6 mRNAs. Our results indicate that Q/R editing of GluR5 and GluR6 mRNAs is structure-, cell type- and time-dependent, and suggest that editing of these mRNAs is not co-regulated.
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PMID:Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation. 1005 61

The purification, characterization, and synthesis of conantokin-R (Con-R), an N-methyl-D-aspartate (NMDA) receptor peptide antagonist from the venom of Conus radiatus, are described. With the use of well defined animal seizure models, Con-R was found to possess an anticonvulsant profile superior to that of ifenprodil and dizocilpine (MK-801). With voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs, Con-R exhibited the following order of preference for NR2 subunits: NR2B approximately NR2A > NR2C >> NR2D. Con-R was without effect on oocytes expressing the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 or the kainate receptor subunit GluR6. In mouse cortical neurons voltage-clamped at -60 mV, Con-R application produced a slowly developing block of inward currents evoked by 10 microM NMDA and 1 microM glycine (IC(50) = 350 nM). At 3 microM, Con-R did not affect gamma-aminobutyric acid- or kainate-evoked currents. Con-R prevented sound-induced tonic extension seizures in the Frings audiogenic seizure-susceptible mice at i.c.v. doses below toxic levels. It was also effective at nontoxic doses in CF#1 mice against tonic extension seizures induced by threshold (15 mA) and maximal (50 mA) stimulation, and it partially blocked clonic seizures induced by s.c. pentylenetetrazol. In contrast, MK-801 and ifenprodil were effective only at doses approaching (audiogenic seizures) or exceeding (electrical and pentylenetetrazol seizures) those required to produce significant behavioral impairment. These results indicate that the subtype selectivity and other properties of Con-R afford a distinct advantage over the noncompetitive NMDA antagonists MK-801 and ifenprodil. Con-R is a useful new pharmacological agent for differentiation between the anticonvulsant and toxic effects of NMDA antagonists.
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PMID:In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus. 1060 79

We hypothesized that overexpression of specific glutamate receptors within the hippocampus would induce seizures and the associated cellular changes seen in temporal lobe epilepsy (TLE). The GluR6 kainate receptor was overexpressed by injecting rat hippocampi with HSVGluR6, a viral vector transducing fully edited GluR6. These animals experienced limbic seizures approximately 4 h following the injection. Control animals injected with HSVlac, a vector expressing beta-galactosidase, did not have seizures. Recordings from hippocampal CA1 pyramidal cells were performed 12 to 48 h and 1 week to 1 month postinjection. We observed nonsynaptic Na(+)-mediated bursting in 77.5% of cells 12 to 48 h following injection of HSVGluR6 but not HSVlac. The synaptic responses were normal in both groups. However, the physiological properties of cells from HSVGluR6-injected hippocampi changed over time. Two weeks following HSVGluR6 injection, synaptic bursts could be evoked, but intrinsic bursting became rare. These changes persisted for at least 1 month. We postulate that this transition from intrinsic to synaptic hyperexcitability may be important in the development of TLE.
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PMID:Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro. 1096 7

To understand the physiological role of kainate receptors and their participation in seizure induction in animal models of epilepsy, it will be necessary to develop a comprehensive description of their action in the CA3 region of the hippocampus. Activation of presynaptic kainate receptors depresses excitatory synaptic transmission at mossy fiber and associational-commissural inputs to CA3 pyramidal neurons (Vignes et al., 1998; Bortolotto et al., 1999; Kamiya and Ozawa, 2000). In this study, we use gene-targeted mice lacking glutamate receptor 5 (GluR5) or GluR6 kainate receptor subunits to identify the receptor subunits that comprise the kainate receptors responsible for presynaptic modulation of CA3 transmission. We found that bath application of kainate (3 microm) profoundly reduced EPSCs at mossy fiber and collateral synapses in neurons from wild-type and GluR5(-/-) mice but had no effect on EPSCs in neurons from GluR6(-/-) mice. These results therefore contrast with previous studies that supported a role for GluR5-containing receptors at mossy fiber and associational-commissural synapses (Vignes et al., 1998; Bortolotto et al., 1999). Surprisingly, at perforant path synapses kainate receptor activation enhanced transmission; this potentiation was abolished in both GluR5 and GluR6 knock-out mice. Kainate receptors thus play multiple and complex roles to modulate excitatory synaptic transmission in the CA3 region of the hippocampus.
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PMID:Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus. 1106 33


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