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)

A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and approximately 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 microM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have Kb values of 0.63 and 0.31 microM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg i.v., respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (approximately -2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.
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PMID:5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors. 935 35

This study was designed to determine whether hippocampal neuronal AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and NMDA (N-methyl-D-aspartate) mRNA levels were differentially increased in temporal lobe epilepsy patients compared with those measured in control tissue from non-seizure autopsies. Hippocampi from hippocampal sclerosis patients (n = 28) and temporal mass lesion cases (n = 12) were compared with those from the autopsies (n = 4), and studied for AMPA GluR1-3 and NMDAR1-2 mRNAs using semi-quantitative in situ hybridization, along with fascia dentata and Ammon's horn neuron densities. Compared with the autopsies, and without correction for neuron counts, the mass lesion cases with neuron densities similar to autopsies showed: (i) significantly increased NMDAR2 hybridization densities for fascia dentata granule cells; (ii) increased AMPA GluR3 mRNA densities for Ammon's horn pyramids; and (iii) similar or numerically increased mRNAs for all other subunits and hippocampal subfields. Compared with the autopsies, hippocampal sclerosis cases with decreased neuron densities showed: (i) significantly decreased AMPA GluR1-2 and NMDAR1-2 hybridization densities for Ammon's horn pyramids and (ii) similar or numerically decreased mRNAs for all other subunits and subfields. However, correcting for changes in neuron densities showed that hippocampal sclerosis patients had increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in the CA2 resistant sector GluR2 mRNA levels were numerically greater than autopsies and mass lesion cases. Furthermore, relative to autopsies both sclerosis and mass lesion hippocampi showed that, in the stratum granulosum, the greatest mRNA increases were in AMPA GluR1 and NMDAR2 compared with the other mRNAs. In chronic temporal lobe seizure patients these results indicate that mass lesion and sclerosis cases show differential increases in hippocampal AMPA and NMDA mRNA levels per neuron compared with autopsies, especially for AMPA GluR1 and NMDAR2 in fascia dentata granule cells. These findings support the hypothesis that temporal lobe seizures are associated with increased ionotropic glutamate receptor mRNA levels and alterations in receptor subunit composition that probably contribute to neuronal hyperexcitability, synchronization and seizure generation.
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PMID:Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. 939 13

Many neurologic disorders are related to congenital or acquired hyperammonemia (HA). Advanced symptoms of HA range from seizures in acute stages to stupor and coma in more chronic conditions, manifesting variable imbalance between the inhibitory and excitatory neurotransmission. Evidence obtained with the use of experimental HA models suggests that acute neurotoxic effects of ammonia are mediated by overactivation of ionotropic glutamate (GLU) receptors, mainly the N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree the KA/AMPA receptors. NMDA receptor-mediated neurotoxicity may be potentiated by impaired control of their function by metabotropic GLU receptors, which are inactivated by ammonia. Prolonged overactivation of the NMDA receptors upon extended ammonia exposure causes their downregulation. The GLU receptor changes may be related to their excessive exposure to extrasynaptic GLU. Ammonia promotes GLU accumulation in the extrasynaptic space by enhancing its release from neurons, and/or by decreasing its reuptake to the nerve endings and astrocytes, where the effect results from inactivation (downregulation) of the astrocytic glutamate transporter GLT1. Excitotoxic effects of ammonia are augmented by increased synthesis of nitric oxide (NO), which is associated with NMDA receptor activation and/or increased synaptic transport of arginine (ARG). A shift toward neural inhibition is promoted by positive modulation of the gamma-aminobutyric acid (GABA)ergic tone resulting from excessive accumulation in the brain of endogenous central benzodiazepine receptor agonists, and from upregulation of astrocytic peripheral benzodiazepine receptors leading to elevated levels of prognenelone-derived neurosteroids, which positively modulate the GABA(A) receptor complex. Inhibitory neurotransmission may also be favored by enhanced release from astrocytes of an inhibitory amino acid, taurine.
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PMID:Roles of neuroactive amino acids in ammonia neurotoxicity. 946 66

While it is well documented that the overactivation of ionotropic glutamate receptors leads to seizures and excitotoxic injury, little is known about the role of metabotropic glutamate receptors (mGluRs) in epileptogenesis and neuronal injury. Intracerebroventricular (i.c.v.) infusion of the group I mGluR specific agonist (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG) (1.5 micromol) to conscious rats produced severe and delayed seizures (onset at 4 hr) in 70% of the animals. The i.c.v. infusion of the group I mGluR non-selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (2 micromol) produced a similar rate of severe seizures, but with an early onset (0.6 hr). The analysis of motor activity showed that 3,5-DHPG elicited higher central stimulatory action than did 1S,3R-ACPD. Histopathological analysis of the hippocampus showed that 3,5-DHPG produced severe neuronal damage mainly in the CA1 pyramidal neurons and, to a lesser extent, in the CA3. Although 1S,3R-ACPD infusion also induced a slight injury of the CA1 and CA3 pyramidal neurons, damage was greater in the CA4 and dentate gyrus cells. In conclusion, the in vivo activation of group I mGluRs with the selective agonist 3,5-DHPG produces hyperexcitatory effects that lead to seizures and neuronal damage, these effects being more severe than those observed after infusion of the non-selective agonist 1S,3R-ACPD.
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PMID:Seizures and neuronal damage induced in the rat by activation of group I metabotropic glutamate receptors with their selective agonist 3,5-dihydroxyphenylglycine. 948 69

It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. Furthermore, because glutamate receptor antagonists, particularly those acting on NMDA receptors, protect effectively in the induction of kindling, it was suggested that they may have utility in epilepsy prophylaxis, for example, after head trauma. However, first clinical trials with competitive and uncompetitive NMDA receptor antagonists in patients with partial (focal) seizures, showed that these drugs lack convincing anticonvulsant activity but induce severe neurotoxic adverse effects in doses which were well tolerated in healthy volunteers. Interestingly, the only animal model which predicted the unfavorable clinical activity of competitive NMDA antagonists in patients with chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating that this model should be used in the search for more effective and less toxic glutamate receptor antagonists. In this review, results from a large series of experiments on different categories of glutamate receptor antagonists in fully kindled rats are summarized and discussed. NMDA antagonists, irrespective whether they are competitive, high- or low-affinity uncompetitive, glycine site or polyamine site antagonists, do not counteract focal seizure activity and only weakly, if at all, attenuate propagation to secondarily generalized seizures in this model, indicating that once kindling is established, NMDA receptors are not critical for the expression of fully kindled seizures. In contrast, ionotropic non-NMDA receptor antagonists exert potent anticonvulsant effects on both initiation and propagation of kindled seizures. This effect can be markedly potentiated by combination with low doses of NMDA antagonists, suggesting that an optimal treatment of focal and secondarily generalized seizures may require combined use of both non-NMDA and NMDA antagonists. Given the promising results obtained with novel AMPA/kainate antagonists and glycine/NMDA partial agonists in the kindling model, the hope for soon having potentially useful glutamate antagonists for use in epileptic patients is increasing.
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PMID:Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. 956 Aug 47

Neuropeptide Y (NPY), a 36-amino acid peptide, is present in some hippocampal interneurons and nerve terminals and seems to modulate glutamatergic transmission in this structure. Earlier studies of some other authors showed an increase in NPY expression in the hippocampus during seizures and activation of ionotropic glutamate receptors. In the present study the effect of metabotropic glutamate receptor (mGluR) stimulation was investigated in rat hippocampus by immunohistochemical methods. It was found that (1S,3R)1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a selective agonist of mGluRs injected into the rat lateral ventricle (1 mumol/10 microliters) or hippocampus (0.1 mumol/1 microliter), 24 h before taking the brains for immunohistochemical studies, induced a significant increase in NPY-immunoreactivity in the hippocampus, especially in the hilar region. The obtained results indicate that mGluRs positively modulate the NPY content in the hippocampal neurons.
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PMID:Activation of metabotropic glutamate receptors increases neuropeptide Y expression in the rat hippocampus. Immunohistochemical studies. 956 36

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

Glutamate release after ischemia, hypoxia and seizure activity plays an important role in stimulating adenosine production and release. We characterized the ionotropic glutamate receptor subtype that regulates adenosine levels in vivo and investigated the role of nitric oxide and free radicals in mediating N-methyl-D-aspartate (NMDA)-induced increases in adenosine levels. Rats received unilateral intrastriatal injections and were sacrificed 15 min postinjection by high-energy focused microwave irradiation (10 kW, 1.25 s). Adenosine levels were measured by high-performance liquid chromatography in ipsilateral and contralateral striata. NMDA and kainic acid dose-dependently increased levels of adenosine whereas (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazol proprionic acid had no effect. The NMDA- and kainic acid-induced increases were blocked by dizocilpine, and the kainic acid response was decreased by 6-cyano-7-nitroquinoxaline-2,3-dione. The effects of NMDA and kainic acid on levels of adenosine were not additive. Intrastriatal L-arginine decreased, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, increased basal adenosine levels. Coadministration of NMDA with L-arginine or NG-nitro-L-arginine methyl ester did not significantly affect NMDA-induced increases in levels of adenosine. N-Tert-butyl-phenylnitrone, a free radical scavenger, reversed L-arginine-induced decreases and NMDA-induced increases in levels of adenosine. Together, these results indicate that NMDA-type ionotropic receptors play an important role in regulating in vivo levels of adenosine in rat striatum and that free radicals, but not nitric oxide, apparently are involved in NMDA-induced increases in levels of adenosine. Conversely, nitric oxide, but not free radicals, apparently exert tonic control over basal levels of endogenous adenosine.
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PMID:Levels of endogenous adenosine in rat striatum. I. Regulation by ionotropic glutamate receptors, nitric oxide and free radicals. 958 May 98

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

Corticotropin releasing hormone (CRH) produces age-dependent limbic seizures in the infant rat. Both the phenotype and the neuroanatomic matrix of CRH-induced seizures resemble the seizures induced by the rigid glutamate analogue, kainic acid (KA), and by rapid amygdala kindling. The experiments described in this study tested the hypothesis that the in vivo proconvulsant effects of CRH require activation of ionotropic glutamate receptors. Non-competitive (+MK-801) or competitive (CGP-39551) antagonists of N-methyl-d-aspartate (NMDA) receptors decreased or eliminated the motor effects of CRH, but electrographic CRH-induced seizures were unaffected. Administration of CRH antagonists did not affect the acquisition or the maintenance of rapid kindling, which are mediated by NMDA and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor activation, respectively. CRH receptor blockers failed to alter the latency or duration of seizures induced by activation of KA receptors, and threshold doses of CRH and KA had additive effects. CRH given repeatedly decreased the convulsant threshold dose of KA, probably via injury to hippocampal neurons. These results suggest that CRH and glutamate increase neuronal excitability via independent mechanisms. Because the proconvulsant effects of CRH are highly specific to the developmental period, glutamate-receptor-independent, CRH-receptor mediated excitation may account for some of the enhanced susceptibility to seizures during this period.
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PMID:The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation. 980 17

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