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)

Some non-DBA2 Albino Swiss mice exhibit noise induced epileptic seizures during a short period of postnatal development. Because N-methyl-D-aspartate (NMDA) glutamate ionotropic receptors are involved in the occurrence of audiogenic seizures, we investigated by in situ hybridization methods, the expression of the different subunits (NR1, NR2A, NR2B, NR2C) of this receptor in the central nucleus of the inferior colliculus (IC), a main relay of the auditory pathways. At postnatal day 20, the NR2C subunit is highly expressed in the IC of convulsive mice, while in non-convulsive mice a slight signal is only found for NR1, NR2A, and NR2B. In adult mice, the NR1 and NR2A signals are observed while the NR2B signal is almost undetectable. The audiogenic susceptibility may be related to the transient expression of the NR2C subunit during a brief neonatal period during which synaptic reorganization happens.
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PMID:N-Methyl-D-aspartate receptor subunits NR1 and NR2C are overexpressed in the inferior colliculus of audiogenic mice. 762 42

To investigate the changes underlying kindling epileptogenesis in the rat hippocampus, the levels of the messenger RNAs encoding for the subunits of the N-methyl-D-aspartate-receptor (1, 2A-D) and the kainate-receptor (1, -2, GluR-5, -6, -7) were determined in hippocampal principal neurons using in situ hybridization techniques and semi-quantitative analysis of the autoradiograms. Schaffer collateral-commissural pathway kindled rats were investigated at three different stages of kindling acquisition, always 24 h after the last stimulation. Furthermore, fully kindled rats were studied at long-term (28 days) after termination of kindling stimulations. NR1 messenger RNA levels were slightly decreased in CA1 area of fully kindled animals. In the fascia dentata region, a minor increase of NR2A and NR2B transcripts was found at all stages of kindling acquisition. KA-2 messenger RNA was enhanced in all hippocampal subfields during kindling development. However, none of these changes persisted at long-term after the last seizure and only the low-abundant GluR-7 expression was slightly depressed in the fascia dentata. From our observations we conclude that it is unlikely that alterations in N-methyl-Daspartate or kainate receptor gene expression play an important role in kindling acquisition or maintenance.
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PMID:N-methyl-D-aspartate and kainate receptor gene expression in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis. 767 86

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. Enhanced function of synapses using the NMDA subtype of glutamate receptor could contribute to the expression of the increased excitability. We previously found that CA3 pyramidal cells of hippocampus of kindled animals exhibit a selective and long-lasting (1 month) increased sensitivity to NMDA-evoked depolarization. The goal of this study was to develop a molecular explanation of the enhanced sensitivity to NMDA. We used radioligand binding studies of membranes isolated from microdissected regions of hippocampus including fascia dentata, CA3, and CA1. We also used quantitative in situ hybridization with subtype-specific riboprobes or oligonucleotides to determine whether increased expression of one or more of the genes encoding NMDA receptors was present in hippocampal granule and pyramidal cells of kindled animals. When studied 28 d after the last evoked seizure, we found that kindling induced a 2.8-fold increase in the number of binding sites for the competitive NMDA receptor antagonist 3-[(+/-)-2-(carboxypiperazine-4-yl)][1,2-3H-]propyl-1-phosphonic acid (3H-CPP). This increase was confined to region CA3 within the hippocampus. Similar, though much smaller, changes were detected 24 hr after the last evoked seizure. Surprisingly, no changes in the binding of another competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)-2-3H-piperidinecarboxylate (3H-CGS-19755), were detected at either time point in any hippocampal region. Transcript levels of the NMDA receptor genes NMDAR1, NR2A, NR2B, NR2C, and NR2D and a glutamate-binding protein (GBP) were not altered by kindling. These findings demonstrate that kindling induces the expression of an NMDA receptor that is novel in that it is recognized by 3H-CPP but not by 3H-CGS-19755. The molecular basis of this novel NMDA receptor is not determined by differential expression of mRNA transcripts of known NMDA receptor genes. The direction, time course, and location of the kindling-induced increase in 3H-CPP binding suggest that this novel receptor may underlie the increased sensitivity of CA3 neurons to NMDA observed in kindled animals.
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PMID:Kindling induces the long-lasting expression of a novel population of NMDA receptors in hippocampal region CA3. 802 71

5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (Kb values) were 0.4 to 0.8 microM in oocytes and approximately 0.6 microM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 microM (1 microM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 microM and Kb values for ACEA-1011 between 0.2 to 0.8 microM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. Kb values were 4 to 9 microM in oocytes and 9 to 10 microM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was approximately 12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
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PMID:Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione: a novel systemically active ionotropic glutamate receptor antagonist. 853 Oct 83

Intense electrical activity throughout the brain which results from generalized epileptic or kindled seizures is thought to cause persistent and widespread neuronal plastic changes. We have previously reported that stage 5 kindled seizures cause an increase in vasopressin messenger RNA content and nitric oxide synthase activity in neuroendocrine cells of the supraoptic nucleus which lasts for at least four months after the last seizure. To evaluate whether changes in the expression of N-methyl-D-aspartate receptor subunits might contribute to these effects, the expression of NR1, NR2A, NR2B. NR2C and NR2D subunit messenger RNAs was examined by in situ hybridization in neuroendocrine cells of the supraoptic nucleus one month after amygdala kindling to stage 5 seizures. No change in NR1 subunit messenger RNA expression was seen. In contrast, NR2B subunit messenger RNA was significantly increased. by about 63%, and NR2D subunit messenger RNA was significantly decreased, by about 22%. indicating a shift in NR2 subunit messenger RNA expression. NR2B subunit messenger RNA was also significantly increased in adjacent limbic structures. The long-lasting shift towards increased NR2B and decreased NR2D messenger RNA expression after kindling suggests that N-methyl-D-aspartate receptor NR2 composition may be an important factor in the maintenance of pathological plasticity following generalized seizures. If these changes in messenger RNA are translated into increased NR2B and decreased NR2D subunits in the N-methyl-D-aspartate receptors in vivo, both a decrease in sensitivity due to a strong magnesium block and an increase in channel ion gating might be predicted.
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PMID:Amygdala kindling alters N-methyl-D-aspartate receptor subunit messenger RNA expression in the rat supraoptic nucleus. 913 Jul 80

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. A diversity of studies demonstrate that kindling results in long lasting (28 days) alterations of the functional and pharmacologic properties of NMDA receptors, indicating that kindling may cause changes intrinsic to the NMDA receptor itself. Our previous studies disclosed no differences in NMDA receptor subunit gene or splice isoform mRNA expression between control and kindled animals 28 days after the last kindled seizure. Here, we extend those earlier studies by measuring levels of subunit protein for NMDAR1, NR2A, and NR2B in the hippocampus of control and kindled animals, 28 days after the last kindled seizure. We report that kindling does not effect long-lasting changes in the levels of NMDA receptor subunit protein. Together these findings support the idea that alterations in NMDA receptor protein expression do not contribute to the novel properties of NMDA receptors induced by kindling.
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PMID:Measurement of NMDA receptor protein subunits in discrete hippocampal regions of kindled animals. 979 76

Chronic ethanol exposure and subsequent withdrawal are known to change NMDA receptor activity. This study examined the effects of chronic ethanol administration and withdrawal on the expression of several NMDA receptor subunit and splice variant mRNAs in the rat cerebral cortex. Ethanol dependence was induced by ethanol vapour exposure. To delineate between seizure-induced changes in expression during withdrawal and those due to withdrawal per se, another group of naive rats was treated with pentylenetetrazol (PTZ) injection (30 mg/kg, i.p.). RNA samples from the cortices of chronically treated and withdrawing animals were compared to those from pair-fed controls. Changes in NMDA receptor mRNA expression were determined using ribonuclease protection assays targetting the NR2A, -2B, -2C and NR1-pan subunits as well as the three alternatively spliced NR1 inserts (NR1-pan describes all the known NR1 splice variants generated from the 5' insert and the two 3' inserts). The ratio of NR1 mRNA incorporating the 5' insert vs. that lacking it was decreased during ethanol exposure and up to 48 h after withdrawal. NR2B mRNA expression was elevated during exposure, but returned to control levels 18 h after withdrawal. Levels of NR2A, NR2C, NR1-pan and both 3' NR1 insert mRNAs from the ethanol-treated groups did not alter compared with the pair-fed control group. No changes in the level of any NMDA receptor subunit mRNA was detected in the PTZ-treated animals. These data support the hypothesis that changes in NMDA receptor subunit composition may underlie a neuronal adaptation to the chronic ethanol-inhibition and may therefore be important in the precipitation of withdrawal hyperactivity.
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PMID:Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex. 1008 58

Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA)-receptor subtype of glutamate receptor in a number of brain areas. The mechanism of ethanol action has been investigated by means of patch-clamp recording of ionic currents and fura-2 measurement of intracellular Ca2+ concentration in cell culture systems; the subunit composition of NMDA receptors and their influence on the effect of ethanol was determined by molecular biology methods. Ethanol does not appear to interact with NMDA either at the glutamate recognition site of the receptor, or at any of the hitherto known multiple modulatory sites, such as the glycine or polyamine site. Moreover, ethanol does not cause an open channel block by itself and fails to interact with Mg2+ at the site where it causes open channel block. The ability of ethanol to inhibit responses to NMDA is dependent on the subunit combination of NMDA receptors. The NR1/NR2A and NR1/NR2B combinations are preferentially sensitive to ethanol inhibition. Chronic treatment with ethanol leads to an increase of the NMDA receptor number at the transcriptional and posttranscriptional level; the receptor function is also facilitated. This causes withdrawal-type seizures after termination of chronic treatment with ethanol. The inhibition of NMDA receptors by ethanol leads to the depression of excitatory synaptic potentials mediated by this type of excitatory amino acid receptor. Ethanol-induced disturbances in certain regions of the brain, i.e. hippocampus, nucleus accumbens or locus coeruleus may lead to cognitive disorders or drug dependence. Brain slices containing the locus coeruleus may be used as an in vitro test system to investigate the addictive properties of ethanol.
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PMID:Ethanol-induced inhibition of NMDA receptor channels. 1040 99

This manuscript summarizes mouse mutants for ionotropic glutamate receptors that were generated by different laboratories to analyze the function of the NMDA and AMPA receptors in the mouse. Thus, NMDA receptor mutant mice that were generated by the "knock-in" technology demonstrate that the NR1 and the NR2B subunits participate in the formation of NMDA receptors that are involved in vital functions like breathing and suckling of a newborn mouse. Mice that lack NR2A, -2C, and -2D subunits were described to be viable and have been used to study the role of NMDA receptors in adult mice. The depletion of the GluR-B subunit revealed an NMDA receptor-independent form of long-term potentiation (LTP). This AMPA receptor-mediated LTP at CA3/CA1 synapses was also observed in mice that carry an editing-deficient GluR-B allele even though these mice die prematurely after heavy epileptic seizures. In other mutants, the intracellular COOH-terminal domain of the NMDA receptor was truncated; and when compared to NMDA receptor "knock-out" mice, a functional knock-out of the NMDA receptor was observed. However, in the synapses of NR2AC/AC mutants, gatable NMDA receptors were synaptically activated, indicating that the knock-out phenotypes mediated by the COOH-terminally truncated NMDA receptors appear to reflect defective intracellular signaling.
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PMID:Mice with genetically modified NMDA and AMPA receptors. 1041 26

Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.
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PMID:Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients. 1048 65


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