UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Felbamate is an anticonvulsant used in the treatment of seizures associated with Lennox-Gastaut syndrome and complex partial seizures that are refractory to other medications. Its unique clinical profile is thought to be due to an interaction with N-methyl-D-aspartate (NMDA) receptors, resulting in decreased excitatory amino acid neurotransmission. To further characterize the interaction between felbamate and NMDA receptors, recombinant receptors expressed in Xenopus oocytes were used to investigate the subtype specificity and mechanism of action. Felbamate reduced NMDA- and glycine-induced currents most effectively at NMDA receptors composed of NR1 and NR2B subunits (IC50 = 0.93 mM), followed by NR1-2C (2.02 mM) and NR1-2A (8.56 mM) receptors. The NR1-2B-selective interaction was noncompetitive with respect to the coagonists NMDA and glycine and was not dependent on voltage. Felbamate enhanced the affinity of the NR1-2B receptor for the agonist NMDA by 3.5-fold, suggesting a similarity in mechanism to other noncompetitive antagonists such as ifenprodil. However, a point mutation at position 201 (E201R) of the epsilon2 (mouse NR2B) subunit that affects receptor sensitivity to ifenprodil, haloperidol, and protons reduced the affinity of NR1-epsilon2 receptors for felbamate by only 2-fold. Furthermore, pH had no effect on the affinity of NR1-2B receptors for felbamate. We suggest that felbamate interacts with a unique site on the NR2B subunit (or one formed by NR1 plus NR2B) that interacts allosterically with the NMDA/glutamate binding site. These results suggest that the unique clinical profile of felbamate is due in part to an interaction with the NR1-2B subtype of NMDA receptor.
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PMID:Subtype-selective antagonism of N-methyl-D-aspartate receptors by felbamate: insights into the mechanism of action. 1021 67

Transcriptional and translational regulation of glutamate receptor expression determines one of the key phenotypic features of neurons in the brain--the properties of their excitatory synaptic receptors. Up- and down-regulation of various glutamate receptor subunits occur throughout development, following ischemia, seizures, repetitive activation of afferents, or chronic administration of a variety of drugs. The promoters of the genes that encode the NR1, NR2B, NR2C, GluR1, GluR2, and KA2 subunits share several characteristics that include multiple transcriptional start sites within a CpG island, lack of TATA and CAAT boxes, and neuronal-selective expression. In most cases, the promoter regions include overlapping Sp1 and GSG motifs near the major initiation sites, and a silencer element, to guide expression in neurons. Manipulating the levels of glutamate receptors in vivo by generating transgenic and knockout mice has enhanced understanding of the role of specific glutamate receptor subunits in long-term potentiation and depression, learning, seizures, neural pattern formation, and survival. Neuron-specific glutamate receptor promoter fragments may be employed in the design of novel gene-targeting constructs to deliver future experimental transgene and therapeutic agents to selected neurons in the brain.
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PMID:Genetic regulation of glutamate receptor ion channels. 1033 Oct 83

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

NR1 and NR2 are the two gene families for the NMDA receptor. In vitro studies show that while NR2 alone is nonfunctional, NR1 alone produces weak currents to glutamate or NMDA. We previously showed by immunocytochemistry (ICC) that in normal appearing, nonepileptic human cortical neurons, only NR1 and not NR2 proteins were expressed, in contrast to the presence of both NR1 and NR2 in normal rat cortical neurons. We also showed, in dysplastic epileptic cortex, that both NR1 and NR2 were highly expressed using ICC on adjacent 30-microm sections. However, the relative coexpressions of NR1 and NR2 proteins in single neurons in single sections of human epileptic cortex were unknown. In this study, we used double-labeled immunofluorescence and confocal microscopy to examine the distribution and coexpression of subunit proteins for NR1 and NR2A/B in both nondysplastic (control comparison) and dysplastic regions of human brain resected for the treatment of intractable epilepsy (11 patients). In nondysplastic regions, cortical neurons did not have immunoreactivity (ir) for NR2A/B, whereas NR1-ir was abundant. By contrast, dysplastic neurons in the regions with epileptic cortical dysplasia showed intense NR2A/B-ir in the somata and their dendritic processes. These same NR2A/B-ir dysplastic neurons were colabeled by NR1. These results demonstrate directly that dysplastic neurons express both NR2A/B and NR1 proteins, whereas nondysplastic cortical neurons express only NR1 proteins. Selective coexpression of NR2A/B and NR1 in dysplastic neurons suggests that NR2A/B may form heteromeric NR1-NR2 coassemblies and hyperexcitability in dysplastic neurons that could contribute to focal seizure onset.
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PMID:Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. 1050 12

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

The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.
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PMID:An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. 1072 77

Repeated injections of a subconvulsant dose of pentylenetetrazole (PTZ, 30 mg/kg IP three times weekly for 13 injections) in Wistar and hooded Lister rats resulted in kindled seizures, the extent of which varied between strains. Wistar rats achieved stage 4 of clonic-tonic seizures, whereas hooded Lister rats only reached stage 2 of convulsive waves axially through the body. Rats were killed 10 days after their final injection, and radioligand binding was used to measure the expression of NMDA receptors in cortex and hippocampus using [3H]MK-801 and [3H]L-689,560, the latter binding specifically to the NR1 subunit. [3H]Ro 15-1788 measured expression of GABA(A)-benzodiazepine binding sites containing alpha1, alpha2, alpha3, or alpha5 subunits. Specific analysis of GABA(A) receptors containing the alpha5 subunit, which are preferentially localized in the hippocampus, was assessed with [3H]L-655,708. In the cortex, there was no effect of strain or treatment on the K(D) or B(max) of any of the ligands. Similarly, there was no effect of strain or treatment on hippocampal [3H]L-689,560 or [3H]Ro 15-1788 binding. However, in the hippocampus there was a significant, albeit modest, effect of treatment on the B(max) of [3H]MK-801 binding and the B(max) and K(D) of [3H]L-655,708 binding, i.e., PTZ-treated rats had fewer [3H]MK-801 and [3H]L-655,708 binding sites (NMDA and alpha5-containing GABA(A) receptors, respectively), but, these reductions were significant only in the relatively seizure-insensitive hooded Lister strain. This suggests that the increased susceptibility to kindling in Wistar rats is not directly related to alterations in the expression of NMDA or GABA(A) receptors.
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PMID:Kindling induced by pentylenetetrazole in rats is not directly associated with changes in the expression of NMDA or benzodiazepine receptors. 1076 32

Although serine proteases and their receptors are best known for their role in blood coagulation and fibrinolysis, the CNS expresses many components of an extracellular protease signaling system including the protease-activated receptor-1 (PAR1), for which thrombin is the most effective activator. In this report we show that activation of PAR1 potentiates hippocampal NMDA receptor responses in CA1 pyramidal cells by 2.07 +/- 0.27-fold (mean +/- SEM). Potentiation of neuronal NMDA receptor responses by thrombin can be blocked by thrombin and a protein kinase inhibitor, and the effects of thrombin can be mimicked by a peptide agonist (SFLLRN) that activates PAR1. Potentiation of the NMDA receptor by thrombin in hippocampal neurons is significantly attenuated in mice lacking PAR1. Although high concentrations of thrombin can directly cleave both native and recombinant NR1 subunits, the thrombin-induced potentiation we observe is independent of NMDA receptor cleavage. Activation of recombinant PAR1 also potentiates recombinant NR1/NR2A (1.7 +/- 0.06-fold) and NR1/NR2B (1.41 +/- 0.11-fold) receptor function but not NR1/NR2C or NR1/NR2D receptor responses. PAR1-mediated potentiation of recombinant NR1/NR2A receptors occurred after activation with as little as 300 pm thrombin. These data raise the intriguing possibility that potentiation of neuronal NMDA receptor function after entry of thrombin or other serine proteases into brain parenchyma during intracerebral hemorrhage or extravasation of plasma proteins during blood-brain barrier breakdown may exacerbate glutamate-mediated cell death and possibly participate in post-traumatic seizure. Furthermore, the ability of neuronal protease signaling to control NMDA receptor function may also have roles in normal brain development.
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PMID:Potentiation of NMDA receptor function by the serine protease thrombin. 1084 28

We previously found gender selective alterations in gene expression for GABA(A) and NMDA receptors associated with the development of ethanol dependence. Males and females have a differing hormonal environment, including steroid hormone derivatives (neuroactive steroids) that exert effects at GABA(A) and NMDA receptors. Therefore, we explored whether the removal of ovarian steroids would alter gender differences in response to chronic ethanol exposure. We found that ovariectomy reduced ethanol drinking levels by 15%, comparable to earlier observations between intact female and male rats. However, investigation of the effects of chronic ethanol exposure on intact versus ovariectomized female rats uncovered few differences in chronic ethanol-induced alterations in selected GABA(A) or NMDA receptor subunit peptide levels. In general, findings for both groups of females were similar to previous observations. There was no reduction in GABA(A) receptor alpha1 subunit levels in cerebral cortex in either intact or ovariectomized female rats, in contrast to the significant reduction observed in male rats. In addition, both intact and ovariectomized female rats had increased levels of the NMDA NR1 subunit in cerebral cortex and hypothalamus, but not in hippocampus, whereas ethanol dependent male rats displayed significant increases in the NR1 subunit only in hippocampus. Radioligand binding analysis with [35S]TBPS found no differences in modulation of the GABA(A) receptor by neuroactive steroids between ethanol dependent male, intact female or ovariectomized female rats. Seizure susceptibility was not different between intact or ovariectomized female rats during ethanol withdrawal. We did observe differential effects on brain allopregnanolone and plasma corticosterone levels between ethanol dependent intact and ovariectomized female rats, suggesting that ovarian steroids influence HPA axis adaptations to prolonged ethanol exposure. Overall, these data suggest that ovarian steroids do not significantly impact the gender selective alterations of GABA(A) and NMDA receptors associated with ethanol dependence.
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PMID:Ovariectomy has minimal effects on neuroadaptations associated with ethanol dependence in female rats. 1087 95

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