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 anticonvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in different seizure models by use of intracerebroventricular infusion. The mGluR1a antagonist/mGluR2 agonist, (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG] dose-dependently antagonized pentylenetetrazol- and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced by electrical stimulation. (+)-alpha-Methyl-4-carboxyphenylglycine showed no anticonvulsant activity in any of the models examined. Agonists of mGluRs which are particularly potent at mGluR2, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine and (1S,3R)-1-aminocyclopentane dicarboxylic acid significantly protected against sound-induced convulsions in DBA/2 mice and DMCM-induced seizures in mice but were inactive against seizures induced by administration of pentylenetetrazol or by electrical stimulation. These data suggest that mGluR ligands modulate seizure activity in mice and this effect may be mediated via antagonism of mGluR1a-type as well as via activation of mGluR2-type mGluRs.
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PMID:Modulation of seizure activity in mice by metabotropic glutamate receptor ligands. 863 17

In guinea pig hippocampal slices, picrotoxin elicited spontaneous epileptiform bursts 300-550 ms in duration. Additional application of (R,S)-3,5-dihydroxyphenylglycine or (S)-3-hydroxyphenylglycine, agonists specific for group I metabotropic glutamate receptors (mGluRs), or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a broad-spectrum mGluR agonist, converted picrotoxin-induced interictal bursts into prolonged discharges measured on the order of seconds. The prolonged discharges induced by selective group I mGluR agonist continued to be produced for hours after agonist removal. The antagonists (S)-4-carboxyphenylglycine and (+)-alpha-methyl-4-carboxyphenylglycine had no effect on the duration of picrotoxin-induced interictal bursts. However, after agonist exposure, the persistent prolonged discharges occurring in the absence of agonist were reversibly suppressed by the antagonists, suggesting that the activity is maintained via endogenous activation of group I mGluRs by synaptically released glutamate. Our results suggest that, under some conditions, activation of group I mGluRs produces long-lasting enhancement of synaptic responses, mediated at least in part by autopotentiation of the group I mGluR response itself, which may result in the production of seizure discharges and contribute to epileptogenesis.
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PMID:Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. 924 3

Neuropeptide Y-Y2 receptor mRNA and binding were investigated after local injection of excitatory amino acid receptor agonists into the rat hippocampus. The general metabotropic glutamate receptor (mGluR) agonist (1S,3R)ACPD (200 and 400 nmol) and the group I mGluR agonist DHPG (50 nmol) enhanced Y2 receptor mRNA levels in granule cells (by up to 470%) and [125I]PYY(3-36) binding in mossy fibers. The group I mGluR antagonist 4-CPG (200 nmol) inhibited the action of (1S,3R)ACPD. On the other hand, AMPA and NMDA enhanced Y2 receptor expression only at neurodegenerative doses (> 0.3 and 3 nmol, respectively). It is suggested that seizure-induced Y2 receptor expression in granule cells may be mediated by group I mGluRs.
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PMID:Metabotropic glutamate receptors mediate activation of NPY-Y2 receptor expression in the rat dentate gyrus. 969 26

To clarify the contribution of metabotropic glutamate (mGlu) receptors in brain to benzodiazepine withdrawal signs, we now examine the effects in mice of selective ligands for three subgroups of mGlu receptor on the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic diazepam treatment. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the group 1 mGlu receptor antagonist, (S)-4-carboxyphenylglycine ((S)-4CPG: 56 and 100 nmol). These doses of (S)-4CPG did not alter the seizure threshold in chronically vehicle-treated (control) mice. Pretreatment i.c.v. with a presynaptic mGlu receptor agonist (the group 2 mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)-glycine (L-CCG-I: 3.0 and 5.6 nmol) and the group 3 mGlu receptor agonist, L-amino-4-phosphonobutyric acid (L-AP4: 3.0 and 5.6 nmol)) failed to suppress the decrease in seizure threshold in diazepam-withdrawn mice, but increased the seizure threshold in control mice. Pretreatment i.c.v. with the group 1 mGlu receptor antagonist/group 2 mGlu receptor agonist, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG: 56 and 100 nmol), significantly increased the seizure threshold in control mice and suppressed the decrease in seizure threshold in diazepam-withdrawn mice. These findings suggest that enhancement of group 1 mGlu receptor function and a decline in both group 2 and group 3 mGlu receptor functions may play an important role in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal.
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PMID:Role of metabotropic glutamate receptors in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. 1020 74

Picrotoxin, an antagonist of GABA(A) receptor-mediated activity, elicited 320- to 475-ms synchronized bursts from the CA3 region of the guinea pig hippocampal slice. The addition of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3, 5-dihydroxyphenylglycine (DHPG, 50 microM; 20- to 45-min application) gradually increased the burst duration to 1-4 s; this effect persisted 2-3 h after agonist removal. To determine whether the induction of this long-lasting effect required ongoing synchronized activity during mGluR activation, DHPG application in a second set of experiments took place in the presence of CNQX and (R, S)-CPP, antagonists of AMPA/kainate and NMDA receptors, respectively. In these experiments, synchronized bursting was silenced during the mGluR agonist application, yet after wash out of the DHPG and the ionotropic glutamate receptor (iGluR) blockers, epileptiform discharges 1-10 s in duration appeared and persisted at least 2 h after wash out of the mGluR agonist. The potentiated bursts were reversibly shortened by application of 500-1,000 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) or (S)-4-carboxyphenylglycine (4CPG), agents with group I mGluR antagonist activity. These data suggest that transient activation of group I mGluRs, even during silencing of synchronized epileptiform activity, may have an epileptogenic effect, converting brief interictal-length discharges into persistent seizure-length events. The induction process is iGluR independent, and the maintenance is largely mediated by the action of endogenous glutamate on group I mGluRs, suggesting that autopotentiation of the group I mGluR-mediated response may underlie the epileptogenesis seen here.
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PMID:Group I mGluR-mediated silent induction of long-lasting epileptiform discharges. 1044 1

Elevated levels of extracellular glutamate ([Glu]o) cause uncontrolled Ca2+ increases in most neurons and are believed to mediate excitotoxic brain injury following stroke and other nervous system insults. In the normal brain, [Glu]o is tightly controlled by uptake into astrocytes. Because the vast majority of primary brain tumors (gliomas) are derived from astrocytes, we investigated glutamate uptake in glioma cells surgically isolated from glioma patients (glioblastoma multiforme) and in seven established human glioma cell lines, including STTG-1, D-54 MG, D-65 MG, U-373 MG, U-138 MG, U-251 MG, and CH-235 MG. All glioma cells studied showed impaired glutamate uptake, with a Vmax < 10% that of normal astrocytes. Moreover, rather than removing glutamate from the extracellular fluid, glioma cells release large amounts of glutamate, resulting in elevations of [Glu]o in excess of 100 microM within hours in a space that is 1000-fold larger than the cellular volume. Exposure of cultured hippocampal neurons to glioma-conditioned medium elicited sustained [Ca2+]i elevations that were followed by widespread neuronal death. Similarly, coculturing of hippocampal neurons and glioma cells, either with or without direct contact, resulted in neuronal death. Glioma-induced neuronal death could be completely prevented by treating neurons with the N-methyl-D-aspartate receptor antagonists MK-801/D(-)-2-amino-5-phosphonopentanoic acid or by depletion of glutamate from the medium. Interestingly, several phenylglycine derivatives including the metabotropic glutamate receptor agonist/antagonist (S)-4-carboxyphenylglycine (S-4CPG) potently and selectively inhibited glutamate release from glioma cells and prevented neurotoxicity. These data suggest that growing glioma tumors may actively kill surrounding neuronal cells through the release of glutamate. This glutamate release may also be responsible in part for tumor-associated seizures that occur frequently in conjunction with glioma. These data also suggest that neurotoxic release of glutamate by gliomas may be prevented by phenylglycine derivatives, which may thus be useful as an adjuvant treatment for brain tumors.
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PMID:Glioma cells release excitotoxic concentrations of glutamate. 1048 87

Elevated levels of extracellular glutamate ([Glu](o)) can induce seizures and cause excitotoxic neuronal cell death. This is normally prevented by astrocytic glutamate uptake. Neoplastic transformation of human astrocytes causes malignant gliomas, which are often associated with seizures and neuronal necrosis. Here, we show that Na(+)-dependent glutamate uptake in glioma cell lines derived from human tumors (STTG-1, D-54MG, D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is up to 100-fold lower than in astrocytes. Immunohistochemistry and subcellular fractionation show very low expression levels of the astrocytic glutamate transporter GLT-1 but normal expression levels of another glial glutamate transporter, GLAST. However, in glioma cells, essentially all GLAST protein was found in cell nuclei rather than the plasma membrane. Similarly, brain tissues from glioblastoma patients also display reduction of GLT-1 and mislocalization of GLAST. In glioma cell lines, over 50% of glutamate transport was Na(+)-independent and mediated by a cystine-glutamate exchanger (system x(c)(-)). Extracellular L-cystine dose-dependently induced glutamate release from glioma cells. Glutamate release was enhanced by extracellular glutamine and inhibited by (S)-4-carboxyphenylglycine, which blocked cystine-glutamate exchange. These data suggest that the unusual release of glutamate from glioma cells is caused by reduction-mislocalization of Na(+)-dependent glutamate transporters in conjunction with upregulation of cystine-glutamate exchange. The resulting glutamate release from glioma cells may contribute to tumor-associated necrosis and possibly to seizures in peritumoral brain tissue.
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PMID:Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. 1059 60

Memory impairment is a common consequence of epileptic seizures. The hippocampal formation is particularly prone to seizure-induced amnesia due to its prominent role in mnemonic processes. We used the isolated CA1 slice preparation to examine effects of seizure-like activity on hippocampal plasticity, long-term potentiation (LTP), and long-term depression (LTD). Repeated spontaneous ictal events, generated in the presence of antagonists of GABA(A) receptor function, led to a stepwise erasure of LTP (termed spontaneous depotentiation, SDP). SDP could be initiated at various stages of LTP consolidation (tested < or =120 min after the induction of LTP). Renewed tetanic stimulation re-established LTP. SDP was remarkably specific: baseline transmission and other forms of hippocampal plasticity, i.e., Ca(2+)-induced LTP and two forms of LTD [(RS)-3,5-dihydroxyphenyglycine (DHPG) mediated and low-frequency stimulation mediated] were not affected by the same type of seizure activity. SDP was blocked in the presence of the group I mGluR antagonist (S)-4-carboxyphenylglycine. The mGluR1 antagonist (S)-(+)-alpha-amino-methylbenzeneacetic acid blocked approximately 80%, the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)-pyridine approximately 30% of SDP. Most efficient implementation of SDP was observed during seizures in the combined presence of the group I mGluR agonist DHPG and the GABA(A) antagonist bicuculline. However, similar ictal activity generated in the presence of DHPG alone did not lead to SDP in the vast majority of recordings. Complete disinhibition and at least partial activation of group I mGluR were necessary conditions for the induction of SDP. The depotentiating pharmacological conditions were accompanied by tonic membrane depolarization of CA1 pyramidal cells. Since hyperpolarization (by negative current injection) prevented intracellular SDP under depotentiating pharmacological conditions and depolarization (by positive current injection) led to selective intracellular SDP in the non-depotentiating seizure protocol of DHPG, it is concluded that cell depolarization was a sufficient condition for seizure-like activity to reverse hippocampal LTP.
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PMID:Reversal of hippocampal LTP by spontaneous seizure-like activity: role of group I mGluR and cell depolarization. 1528 58