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)

The neurotoxic and convulsant properties of conformationally restricted and synthetic analogues of excitatory acidic amino acids were examined after stereotaxic injection into the striatum and the dentate gyrus of the hippocampal formation. In the striatum, neurotoxicity was quantified by the reduction in the activity of choline acetyltransferase and glutamate decarboxylase, markers for striatal intrinsic neurons. The following sequence of neurotoxic potencies was defined; kainic acid approximately equal to domoic acid much greater than alpha-keto kainic acid approximately equal to alpha-allo kainic acid greater than ibotenic acid approximately equal to cis-cyclopentyl glutamic acid greater than quisqualic acid approximately equal to N-methyl-D-aspartic acid. When normalized for neurotoxic potencies, a wide variation in the convulsant effects of the agents was observed after hippocampal injection. N-Methyl-D-aspartate produced nearly continuous electroencephalographic seizures for 2 hr after injection, where alpha-keto-kainate and kainate and quisqualate caused seizure activity for 64 and 45% respectively of this period; kainate, alpha-allo kainate and domoate caused intermittent seizure activity during approximately 30% of the recording period; ibotenate and cyclopentylglutamate had minimal convulsant effects. Seizures were associated with a significant reduction in the levels of norepinephrine and with increases in the levels of 5-hydroxyindoleacetic acid in the cortex and hippocampal formation and increases in the levels of gamma-aminobutyric acid in the hippocampal formation. Kainate, domoate, keto-kainate and alpha-allo-kainate caused extensive lesions of the hippocampal formation that also involved the pyriform cortex; ibotenate and cyclopentylglutamate caused uniform but substantial lesions limited to the dentate gyrus, whereas quisqualate and N-methyl-D-aspartate produced small and restricted lesions. The results demonstrate a poor correlation between the neurotoxic and convulsant potencies of these excitatory amino acid analogues and suggest that receptor-specific interactions may account for these disparities.
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PMID:Excitatory amino acid analogues: neurotoxicity and seizures. 706 5

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.
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PMID:A new experimental model of epilepsy based on the intraventricular injection of endothelin. 750 66

Glutamic acid has been believed to be an excitatory transmitter in the mammalian central nervous system (CNS), and has been implicated in the pathogenesis of neuronal damage in the mammalian CNS. There are two major classes of glutamate receptors, ionotropic (iGluR) and metabotropic glutamate receptors (mGluR). Participation of iGluRs in glutamate mediated neurotoxicity has been well documented. However, much less is known about participation of mGluRs than the case for iGluRs. The physiological roles of mGluRs have been believed to regulate transmitter release and to modulate the function of iGluRs through activating various intracellular second messenger system. Recently we have discovered several potent agonists for mGluRs which would provide additional information about glutamate mediated neurotoxicity. DCG-IV, one of the most potent mGluR agonists, alleviated kainate-induced limbic motor seizures in extremely low doses in the rat, but the dose response curves showed a bell typed one. DCG-IV also demonstrated severe sedative condition and markedly prolonged the sleeping time in halothane anesthesia. DCG-IV depressed the duration of after-discharges and the seizures evoked by electrical stimulation in the amygdala kindling rat. DCG-IV significantly decreased in number of kainate-induced degenerated neurons in the area of hippocampal CA1, amygdala and septum when DCG-IV was continuously applied into the ventricule. In conclusion, activation of mGluRs leads the alleviation of neuron damage induced by iGluR agonists.
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PMID:[Excitatory amino acids and neuronal death]. 772 52

Homocysteine induces seizures in adult, as well as in immature, experimental animals, but the mechanism of its action is still unknown. The aim of the present study was to examine whether homocysteine in immature animals may act via excitatory amino acids receptors. Seizures were induced in 7-day-old rats by ip administration of homocysteine (16.5 mmol/kg) and the effects of selected antagonists at NMDA and non-NMDA receptor sites were investigated. The anticonvulsant effect was evaluated not only in terms of behavioral changes, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding approximately to 15-30 min after homocysteine administration. Comparable time intervals were used for sacrificing pups in the groups with protective drugs. Non-NMDA antagonists, L-glutamic acid diethylester (GDEE) (4 mmol/kg, ip) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX) (two doses, 30 mg/kg each, ip), failed to protect neonatal rats against homocysteine-induced seizures. Although NBQX prevented the tonic phase, the severity of clonic movements was even more pronounced. Metabolic changes accompanying the seizures (decreases of glucose and glycogen and a rise of lactate) were also not influenced by GDEE or NBQX pretreatment. On the contrary, NMDA antagonists, both competitive (AP7, 0.33 mmol/kg, ip) and noncompetitive (MK-801, 0.5 mg/kg, ip), had a clear-cut anticonvulsant effect. They not only suppressed the behavioral signs of seizures, but also prevented most of the metabolic changes accompanying seizures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NMDA and not non-NMDA receptor antagonists are protective against seizures induced by homocysteine in neonatal rats. 786 64

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

The electroencephalographic and histopathological changes following intra-amygdaloid injection of excitatory amino acids were examined in rats. Limbic seizure status was induced after injection of kainic acid (KA), domoic acid (DA), quisqualic acid (QA), alpha-allo-kainic acid (ALLO-KA) and D-glutamic acid (D-GA). The excitatory effect was found to be in the following order: KA > DA >> QA > ALLO-KA >> D-GA. D-GA caused only a transient paroxysmal discharge on EEG. However, seizure was not induced by an injection of L-glutamic acid (L-GA), D-aspartic acid (D-AA) and L-aspartic acid (L-AA). The minimum epileptogenic doses of these amino acids were defined and intra-amygdaloid injection of these doses were performed. Seven days following the injections, histopathological study was performed. These injection resulted in various degree of degeneration and neuronal cell loss of the pyramidal cells in the ipsilateral hippocampus in the following order of severity: DA > or = KA > D-GA > ALLO-KA > QA. These results indicate absence of correlation between epileptogenicity and histopathological changes. Non epileptogenic amino acids induced no pathological changes of hippocampus or the injected site. These results suggest that the severity of hippocampal damage induced by intra-amygdaloid injection of amino acids depends not only on the magnitude of the induced limbic seizure status but also on the difference of neuropharmacological properties of those amino acids in terms of the interaction with their receptors. Further studies are necessary to elucidate the mechanism of actions of these excitatory amino acids in relation to their receptor subtypes.
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PMID:[Epileptogenicity and neurotoxicity induced by intra-amygdaloid injection of various excitatory amino acids in rats]. 832 16

Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine-dependent seizures (?glutamic acid decarboxylase deficiency) (> 50 patients); (2) GABA-transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain-specific dipeptide of GABA and L-histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA-transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.
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PMID:Inherited disorders of GABA metabolism. 841 16

N-methyl-D-aspartate (NMDA) receptor antagonists are anticonvulsant drugs with specific activity against tonic-clonic pentylenetetrazol-induced seizures. However, they do not affect clonic seizures with preserved righting reflexes. In these experiments, we tested the anticonvulsant activity of strychnine-insensitive glycine receptor (at the NMDA site) antagonist kynurenic acid and nonspecific excitatory amino acid receptor antagonist glutamic acid diethylester (GDEE) in the pentylenetetrazol-induced seizure model in developing rats 7, 12, 18, 25, and 90 days old. Control rats were injected with pentylenetetrazol (100 mg/kg subcutaneously). Other rats were pretreated either with kynurenic acid (40, 80, or 240 mg/kg IP) or with GDEE (0.48-480 mg/kg IP), followed by pentylenetetrazol (100 mg/kg). In very young rats (7 and 12 days), both kynurenic acid and GDEE increased the incidence of clonic seizures, whereas the occurrence of tonic-clonic seizures was suppressed or delayed compared to controls. This effect is very similar to the anticonvulsant action of the competitive and noncompetitive NMDA receptor antagonists. In adult rats, the pretreatment with rather higher doses of kynurenic acid or GDEE suppressed or delayed clonic seizures as well as tonic-clonic seizures. Both drugs also induced behavioral side effects: repetitive orientation, wet dog shakes, and frequent jumping. Our data show that there are only weak and nonconsistent age-specific anticonvulsant effects resulting from the blockade of strychnine-insensitive glycine receptor often associated with serious side effects, thus decreasing chances to develop effective antiepileptic treatment in this drug class.
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PMID:Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis: III. The action of kynurenic acid and glutamic acid diethylester. 859 73

Temporal lobe epilepsy is the most common form of epilepsy. Decreased GABA-ergic inhibition has been suggested as one cause of hyperexcitability. On the other hand, increased expression of glutamic acid decarboxylase, the rate-limiting enzyme of GABA synthesis, has been found in interneurons of the hippocampus in patients with temporal lobe epilepsy and in rats after kainic acid-induced limbic seizures, indicating increased GABA-ergic transmission. Here we report differential expression of two genes encoding different molecular forms of glutamic acid decarboxylase (GAD), GAD65 and GAD67, after kainic acid-induced seizures in the rat. There is a rapid but transient elevation of GAD67 mRNA levels in granule cells 6-24 h after kainic acid injection, followed by enhanced GAD immunoreactivity in the terminal field of mossy fibers. In interneurons in the hilus of the dentate gyrus, a sustained and progressing increase in the expression of both GAD65 and GAD67 messenger RNA occurs. These observations indicate that consitutively glutamatergic mossy fibers may be capable of synthetizing and utilizing the inhibitory transmitter GABA in sustained limbic seizures. Enhanced expression of glutamic acid decarboxylases within interneurons and in granule cells/mossy fibers suggest augmented GABA-ergic neurotransmission supporting selfprotective, anticonvulsive mechanisms in limbic epilepsy.
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PMID:Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. 859 41

Systemic administration of kainic acid (KA), an analogue of glutamic acid, causes limbic seizures and pathophysiological changes in adult rats that are very similar to human temporal lobe epilepsy. One of the earliest changes in gene expression after treatment with KA is the induction of immediate-early genes. The fos and jun families are frequently studied immediate-early genes that are induced by KA. Several groups, including ours, have recently reported that a 35-kDa Fos-related antigen (FRA) is induced for a protracted time by various stimuli. It has been suggested that this FRA is delta FosB, which has a molecular mass of approximately 35 kDa. The present study characterizes the long-term expression of FRA and delta FosB after systemic treatment with KA. Immunocytochemistry and western blot analysis using an antibody that cross-reacts with all known FRAs showed that a 35-kDa FRA was induced at high levels in both the hippocampus and striatum for up to 1 month by KA. A semiquantitative PCR analysis showed that delta FosB was induced by KA, but its expression lasted for only 6 h. This result was also verified by northern blot analysis. These results suggested that the 35-kDa FRA with long-term elevated levels seen with western blot analysis and immunocytochemistry is a new species of the FRA and not delta FosB. The long-term expression of FRA in both the hippocampus and striatum may be associated with the pathophysiological changes after KA administration.
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PMID:Long-term expression of Fos-related antigen and transient expression of delta FosB associated with seizures in the rat hippocampus and striatum. 897 35

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