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

Experiments were carried out to test whether changes in the sensitivity of hippocampal pyramidal neurons to the neurotransmitters glutamate, GABA and noradrenaline may be associated with the establishment of an epileptogenic focus induced by kindling. The effects of iontophoretically applied neurotransmitters on the firing rate of single units were quantified in the rat hippocampal CA1 area in kindled and control animals. Kindling was induced by electrical tetanic stimulation of the Schaffer collateral/commissural fibers. Firing was evoked by local glutamate iontophoresis while simultaneous GABA or noradrenaline application suppressed this response. A significant reduction of the GABAergic inhibitory action on the firing rate in kindled animals studied around four or around 42 days after the last convulsion was found. In the same neurons, the suppressive effect of noradrenaline was not different from controls. The neurons of kindled animals, investigated around four days after the last seizure, had a reduced sensitivity for glutamate; more glutamate ejection current was needed to evoke firing or to evoke the maximum firing rate. In contrast, the responsiveness for glutamate was significantly increased long-term after the last convulsion. These findings demonstrate that hippocampal Schaffer collateral kindling is associated with a long-lasting reduced effectiveness of the GABA-mediated response on glutamate-evoked firing in CA1.
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PMID:A long-lasting decrease in the inhibitory effect of GABA on glutamate responses of hippocampal pyramidal neurons induced by kindling epileptogenesis. 187 Jun 98

An examination of the cellular and molecular mechanisms of neuronal cell damage may lead to the design of pharmacologic interventions during presumed or actual fetal asphyxia. Hypoxia-ischemia in its severest form results in insufficient adenosine 5'-triphosphate production. The most important effect of this is failure of adenosine 5'-triphosphate-dependent membrane functions, which maintain ionic homeostasis, that is, ionic pumping. There is K+ efflux and Na+ influx across the cell membrane, depolarization of the cell membrane, opening of the voltage-dependent calcium channels, and entrance of Ca++ into the cell. Cytosolic Ca++ is also increased by Ca++ efflux from the mitochondria and the sarcoplasmic reticulum. Ca++ is a toxin in high cytosolic concentrations; it activates phospholipases A and C, which cause membrane breakdown and release of free fatty acids, including arachidonic acid. The membrane is damaged, lysis occurs, and the neuron dies. High cytosolic Ca++ also causes release of excitatory amino acids (especially glutamate), which overwhelm the suppressant neurotransmitters, causing seizures, increased metabolism, and aggravation of the insufficient adenosine 5'-triphosphate availability. Thromboxane A2 is generated from arachidonic acid, increasing smooth muscle tone and thereby worsening the ischemia. Cyclooxygenase activity also results in formation of oxygen-free radicals that contribute to cell membrane damage, lysis, and death. Possibilities for pharmacologic interventions include (1) calcium channel blockers and antagonists, (2) excitatory neurotransmitter blockers, (3) oxygen-free radical scavengers (e.g., superoxide dismutase), (4) cyclooxygenase or prostaglandin synthesis inhibitors, and (5) seizure suppressants (e.g., phenobarbital). Some of these treatments have been shown experimentally to limit neuronal death in the adult and fetus, and after more investigative work they may be applicable to clinical practice.
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PMID:Mechanisms of asphyxial brain damage, and possible pharmacologic interventions, in the fetus. 190 82

Recently, the presence of two high affinity binding sites for phencyclidine were described in guinea pig brain, with one site coupled to the glutamate excitatory amino acid receptor, specifically activated by N-methyl-D-aspartate (NMDA) (site 1) and the other site associated with the dopamine (DA) reuptake carrier (site 2). Phencyclidine and its analogs, as well as the benzomorphan opiates, are known to interact with binding sites for phencyclidine. In this study, the equilibrium dissociation constants (Kd) of these compounds for the two binding sites for phencyclidine were determined. Phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), an analog of PCP, were essentially non-selective between the two sites and also were the two drugs of the group observed to have the highest affinity for site 2. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine [(+)MK801] was the most selective agent for site 1, while none of the drugs tested showed selectivity for site 2. In humans, phencyclidine produces psychotomimetic effects, while (+)MK801 has been reported to produce minimal, if any, psychotomimetic effects, at doses sufficient to reduce seizures. These clinical observations, in conjunction with the present biochemical binding data, suggest that (+)MK801 may serve as a "marker" for site 1 and that the psychotomimetic effects of phencyclidine might be mediated by site 2.
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PMID:Specificity of phencyclidine-like drugs and benzomorphan opiates for two high affinity phencyclidine binding sites in guinea pig brain. 196 80

I have reviewed information pertaining to the acidic amino acid analogs of glutamate that have neurotoxic (excitotoxic) activity and pointed out that kainate is the most potent excitotoxin that has been subjected to intensive investigation. Although there is very little published evidence pertaining to domoate neurotoxicity, all available evidence supports the conclusion that the neuroactive properties of domoate are mediated through kainate receptors. Preliminary evidence that domoate powerfully induces a kainate-like seizure-brain damage syndrome in experimental animals further supports involvement of kainate receptors in domoate neurotoxicity. Moreover, the close similarity between this neurotoxic syndrome in experimental animals and the clinical picture witnessed in Canadian victims of mussel poisoning lends further credence to the assumption that this poisoning incident was caused by an interaction between the domoate molecule and kainate receptors in the human central nervous system.
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PMID:Excitotoxicity: an overview. 196 79

Full limbic seizures were kindled in rats by repeated, bi-daily microinjections of glutamate (1.5 mumol) into the basolateral amygdala. Co-administration of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-7-phosphonoheptanoic acid with the glutamate, prevented the development of both electroencephalographic and motor signs of the kindling response. These results indicate an important functional role for NMDA receptors in the development of excitatory amino acid-induced kindling.
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PMID:NMDA receptor blockade inhibits glutamate-induced kindling of the rat amygdala. 196 70

Rats were kindled to two consecutive class 5 seizures by once-daily entorhinal electrical stimulation. After one stimulus-free month, in vitro Ca2(+)-dependent, K(+)-stimulated endogenous amino acid release was measured in regio superior, regio inferior and dentate gyrus of the hippocampal formation. Ca2(+)-dependent L-glutamate release was robust in all 3 regions of controls and greatest in dentate gyrus; release of GABA and L-aspartate were significant in regio superior and dentate gyrus. L-Glutamate release was significantly enhanced in ipsilateral regio inferior of kindled hippocampus and tended to be greater contralaterally. This pattern was not seen in regio superior or dentate gyrus. These studies, in concert with others, suggest that Ca2(+)-dependent L-glutamate release in hippocampus is augmented by entorhinal kindling and that this enhanced release may be primarily from presynaptic granule cell mossy fiber projections.
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PMID:Entorhinal kindling permanently enhances Ca2(+)-dependent L-glutamate release in regio inferior of rat hippocampus. 196 56

Kainic acid was injected into the hippocampus of rats and glutamine synthetase was measured to determine whether astrocytes are involved in the early effects of this neurotoxic agent. Glutamine synthetase was reduced by 38%, 24 h after the stereotaxic application of 4 nmol of kainic acid to this region. The reduction in glutamine synthetase by kainic acid was not due to direct inhibition of the brain enzyme. This effect also was not due to seizure activity since rats peripherally injected with a convulsant dose of kainic acid were found to have normal hippocampal glutamine-synthetase activity. Exposure of astrocyte cultures to kainic acid for 24 h produced no evidence of gliotoxicity and no change in glutamine synthetase activity. The effect of intrahippocampal kainic acid on glutamine synthetase appears to be indirect, most likely produced secondarily to its neuronal effects. Several studies have shown that endogenous glutamate is involved in kainate neurotoxicity. A reduction in glutamine synthetase by kainic acid may impair the capacity for astrocytes to metabolize glutamate. Such an impairment could contribute to the glutamate-mediated cell death following kainic acid exposure.
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PMID:Intrahippocampal kainic acid reduces glutamine synthetase. 197 Jun 31

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.
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PMID:Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. 207 68

1. The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2. Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-((+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nM, and was 4, 5 and 7 fold more potent than the antagonists [+/-)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3. CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4. In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CA1 pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10 microM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. 5. CGP 37849 and CGP 39551 suppressed maximal electroshock-induced seizures in mice with ED50 s of 21 and 4 mg kg'- p.o., respectively. 6. CGP 37849 and CGP 39551 are potent and competitive NMDA receptor antagonists which show significant central effects following oral administration to animals. As such, they may find value as tools to elucidate the roles of NMDA receptors in brain function, and potentially as therapeutic agents for the treatment of neurological disorders such as epilepsy and ischaemic brain damage in man.
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PMID:CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity. 197 95

Methods of thin-layer chromatography with the following elution and photometry were used to determine the amount of taurin, glycin and glutamate in mouse brain 20 and 60 min after injections of arecolin (10 mg/kg), nicotin (9 mg/kg), fluorostigmin (3 mg/kg) and picrotoxin (8 mg/kg). It was determined that seizures induced by these drugs are followed by raising of the levels of taurin (on 20-70%), glycin (after 60 min on 30-70%), glutamate (after 20 min--on 70-60%). The level of glutamate was lowered (by 40-80%) to 60 min after injections of nicotin, fluorostigmin and picrotoxin.
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PMID:[Changes in the content of neuromediator amino acids in the brain of mice with a convulsive syndrome induced by the hyperactivation of CNS cholinergic structures]. 197 59


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