Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early Pb exposure is known to disrupt the development of the hippocampus and result in deficits in learning and memory capacities and altered seizure susceptibility. The excitatory amino acid, NMDA, is found in high concentrations in the hippocampus and has been implicated in learning and memory functions and seizure activity. Rat pups nursed mothers exposed to high (4%), moderate (0.4%), or low (0.05%) levels of PbCO3 in their diet, or a Na2CO3 control diet from postnatal day 1 (P1) to P25. Rat pups were injected with varying doses of NMDA on P15 or P25. Control animals showed a characteristic slowly developing response to NMDA, usually including tail twitches and wet dog shakes at approximately 10 and 40 mg/kg at P15 and P25, respectively, with status epilepticus and death occurring at 40 and 80 mg/kg. Lead-exposed animals displayed an altered sensitivity to NMDA, with high and medium Pb animals showing the onset of behavioral signs and death at lower NMDA doses, the degree of which being dependent on the level of Pb exposure. Low Pb-exposed animals showed a more variable and attenuated response to NMDA. The data are discussed in terms of the possible mechanisms of Pb neurotoxicity.
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PMID:Altered sensitivity to NMDA following developmental lead exposure in rats. 140 40

The behavioral and electroencephalographic effects of N-methyl-D-aspartate (NMDA, 25 nmol/1 microliter) injection into the massa intermedia (MI) was examined in rats. The injection caused violent running/jumping and shrill vocalization without evidence of EEG seizure in the hippocampus (HP) and amygdala (AM). Animals with the injection site located in the reuniens nucleus subsequently developed generalized tonic and then clonic seizure, leading to fatal status epilepticus in some animals. Intermittent or continuous EEG discharge in the limbic system was found during clonic seizures. These findings suggest that the NMDA receptor in the reuniens nucleus in the MI participates in the generation and expression of convulsive seizure in rats.
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PMID:Convulsive seizures in rats induced by N-methyl-D-aspartate injection into the massa intermedia. 152 Nov 46

During status epilepticus provoked by an intra-amygdala injection of kainic acid, the severity of seizures and of consequent neuronal damage was considerably increased in rats treated with L-NOARG, at a dose which completely inhibited NO synthesis. We propose that the effects of L-NOARG could be related to the loss of a retrograde inhibition exerted by NO on NMDA receptors. The complete suppression of NO formation in the brain finally facilitated the development and the generalization of seizures and their neurotoxic consequences.
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PMID:L-nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats. 769 12

Recent evidence suggests that hippocampal damage can be both the result of seizure activity and the cause of further chronic epilepsy. A review of current models of status epilepticus-induced brain damage reveals that excitotoxic mechanisms probably mediate the lesions in most brain regions. NMDA receptors appear to play a dominant role, although non-NMDA glutamate receptors are important in several specific neuronal populations. In the immature brain, a number of unique metabolic features determine a different set of vulnerabilities, resulting in a brain which is more resistant than the adult's to certain mechanisms of brain damage, but quite vulnerable to others. The inhibition of growth by severe seizure activity has implications for the developing brain that have not yet been fully explored. The mechanisms by which seizure-induced hippocampal lesions cause chronic epilepsy have been explored in several recent animal models. A rearrangement of hippocampal circuits may result from death of selected populations of inhibitory neurons, or from misdirected regeneration by excitatory neurons. It could lead to chronic epilepsy through loss of normal inhibition, through sprouting of new excitatory connections, through conservation of excitatory connections which in a healthy brain would be pruned during development, or through facilitation of kindling by one of these mechanisms. These recent results are beginning to reconcile the pathology seen in human hippocampi ablated for intractable epilepsy with that observed in experimental animals, and offer the promise of even greater advances in the future. They suggest a mechanism for Gower's dictum that "seizures beget seizures" and highlight the importance of the interneurons of the dentate gyrus in epileptogenesis.
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PMID:Seizures, brain damage and brain development. 781 23

We used a 24 h perforant path stimulation model of status epilepticus to study the role of non-NMDA receptors in the loss of hilar interneurons and paired pulse inhibition associated with the model. In one experiment, NBQX administered i.v. at 1.0 mg/kg/h significantly reduced the loss of hematoxylin and eosin-stained hilar neurons from 360.2 to 125.3 but failed to protect against the loss of paired pulse inhibition. In a second experiment, i.v. NBQX at 1.5 mg/kg/h significantly protected against loss of SS- and NPY-positive hilar interneurons but also failed to protect against loss of paired pulse inhibition. These results demonstrate that the neuronal loss associated with sustained stimulation of this excitatory pathway is mediated in part through non-NMDA receptors. The lack of protection against loss of paired pulse inhibition suggests that SS- and NPY-immunoreactive interneurons may not be responsible for frequency-dependent paired-pulse inhibition of dentate granule cells.
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PMID:Selective protection of neuropeptide containing dentate hilar interneurons by non-NMDA receptor blockade in an animal model of status epilepticus. 803 45

The amino acids L-glutamate and L-aspartate have been shown to be excitatory neurotransmitters in mammalian central nervous systems. Antagonists acting selectively at excitatory amino acid receptors have shown antiepileptic properties in several animal models. We report the results of the first therapeutic trial of the competitive NMDA antagonist, D-CPP-ene (SDZ EAA-494), in eight patients with intractable complex partial seizures. All patients withdrew prematurely because of side-effects, including poor concentration (8), sedation (7), ataxia (6), depression (3), dysarthria (2), amnesia (2) and unilateral choreo-athetosis in a patient with contralateral Sturge-Weber syndrome. Seizures were unchanged in four patients and worse in three. A further patient with apparent improvement in seizures in the first week developed complex partial status epilepticus on withdrawal of DCPP-ene. EEG on treatment (5) or in the immediate post-treatment period (2) showed slowing of background activity and, in five cases, an increase in epileptiform activity. Serum concentrations of DCPP-ene were found to be unpredictable and higher than expected from pharmacokinetic data on normal subjects. There was no clear relationship between serum concentrations and the severity of side-effects. Preliminary experience with DCPP-ene in patients with refractory partial seizures is not promising. Evaluation of related compounds is warranted.
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PMID:The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. 826 15

Neurons undergoing delayed neuronal death produced by hypoxia-ischaemia (HI) or status epilepticus (SE) showed a massive expression of c-Jun in their nuclei 24 h after the insult. With SE there was also a weaker induction of c-Fos and Jun B in dying neurons. SE induced in the presence of the NMDA antagonist MK-801 produced no delayed c-Jun expression in the hippocampus and nerve cell death did not occur in this region, although there was a delayed c-jun expression in the amygdala/piriform region, and cell death occurred in this area. Activation of central muscarinic receptors with pilocarpine, or block of D2 dopamine receptors with haloperidol, treatments which do not cause neuronal damage, strongly induced Fos and Jun B in hippocampal and striatal neurons, but only induced c-Jun very weakly. Thus, c-Jun may participate in the genetic cascade of events that produce programmed cell death in neurons.
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PMID:Is c-Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? 832 31

Prolonged seizures have long been known to be associated with cell injury and cell death in brain. Such seizure-related neuronal injury has been assumed to be mediated by glutamate, the same excitatory amino acid in the central nervous system which propagates the seizure itself. Elevated extracellular concentrations of glutamate have not been demonstrated in brain during seizures in experimental animals. However, these studies have not been performed during status of a duration adequate to induce cell injury, a time when the putative neurotoxins might be demonstrable. We therefore induced status epilepticus (recorded both with conventional surface EEG and with deep electrodes in the area of greatest vulnerability, the piriform cortex) and lengthened the time of status to the point of cell death. Seizures were induced with intravenous kainic acid, and prolonged by injecting the NMDA antagonist AP-7 into the substantia nigra. Microdialysis probes were introduced into the piriform cortex of one hemisphere to assess the presence of extracellular glutamate. In the contralateral hemisphere the degree of neuronal injury was estimated by measurement of heat shock protein (HSP) expression and cell death quantified by acid fuchsin staining. In this model, neuronal injury correlates linearly with seizure duration; however, elevation of glutamate in the extracellular space was not seen even when neuronal injury was profound.
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PMID:The role of excitatory neurotransmitters in seizure-induced neuronal injury in rats. 893 Mar 50

The present study investigates the role of pharmacologic blockade of NMDA (N-methyl-D-aspartate) and non-NMDA receptors at deep prepiriform cortex (area tempestas, AT) in neuronal injury during prolonged seizures in rat. Status epilepticus was induced by intravenous kainate (15 mg/kg) and neuronal death was assessed in hippocampal CA3 sector 72 h following status epilepticus. Unilateral equimolar microinjections of 2-amino-7-phosphonoheptanoic acid (AP-7), an NMDA receptor antagonist, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), a non-NMDA receptor antagonist, into AT were given prior to kainate administration. Counts of surviving cells in CA3 ipsilateral to NBQX-injected AT were significantly greater than on the contralateral control-side, but no significant difference between the AP-7-injected and saline-injected side was found. These results indicate that neurotransmission via non-NMDA receptors is more important than that via NMDA receptors at AT in the genesis of neuronal injury in hippocampus during kainate-induced status epilepticus.
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PMID:Non-NMDA but not NMDA blockade at deep prepiriform cortex protects against hippocampal cell death in status epilepticus. 912 42

We investigated whether entorhinal cortex (EC) layer IV neurons are hyperexcitable in the post-selfsustaining limbic status epilepticus (post-SSLSE) animal model of temporal lobe epilepsy. We studied naive rats (n = 44), epileptic rats that had experienced SSLSE resulting in spontaneous seizures (n = 45), and electrode controls (n = 7). There were no differences between electrode control and naive groups, which were pooled into a single control group. Intracellular and extracellular recordings were made from deep layers of EC, targeting layer IV, which was activated by stimulation of the superficial layers of EC or the angular bundle. There were no differences between epileptic and control neurons in basic cellular characteristics, and all neurons were quiescent under resting conditions. In control tissue, 77% of evoked intracellular responses consisted of a short-duration [8.6 +/- 1.3 (SE) ms] excitatory postsynaptic potential and a single action potential followed by gamma-aminobutyric acid-A (GABAA) and GABAB inhibitory post synaptic potentials (IPSPs). Ten percent of controls did not contain IPSPs. In chronically epileptic tissue, evoked intracellular responses demonstrated prolonged depolarizing potentials (256 +/- 39 ms), multiple action potentials (13 +/- 4), and no IPSPs. Ten percent of epileptic responses were followed by rhythmic "clonic" depolarizations. Epileptic responses exhibited an all-or-none response to progressive increases in stimulus intensity and required less stimulation to elicit action potentials. In both epileptic and control animals, intracellular responses correlated precisely in morphology and duration with extracellular field potentials. Severing the hippocampus from the EC did not alter the responses. Duration of intracellular epileptic responses was reduced 22% by the N-methyl--aspartate (NMDA) antagonist (-)-2-amino-5-phosphonovaleric acid (APV), but they did not return to normal and IPSPs were not restored. Epileptic and control responses were abolished by the non-NMDA antagonist 6, 7-dinitroquinoxaline-2-3-dione (DNQX). A monosynaptic IPSP protocol was used to test connectivity of inhibitory interneurons to primary cells by direct activation of interneurons with a stimulating electrode placed near the recording electrode in the presence of APV and DNQX. Using this protocol, IPSPs similar to control (P > 0.05) were seen in epileptic cells. The findings demonstrate that deep layer EC cells are hyperexcitable or "epileptiform" in this model. Hyperexcitability is not due to interactions with the hippocampus. It is due partially to augmented NMDA-mediated excitation. The lack of IPSPs in epileptic neurons may suggest inhibition is impaired, but we found evidence that inhibitory interneurons are connected to their target cells and are capable of inducing IPSPs.
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PMID:Responses of deep entorhinal cortex are epileptiform in an electrogenic rat model of chronic temporal lobe epilepsy. 965 44


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