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)

We used the pilocarpine model of chronic spontaneous recurrent seizures to evaluate the time course of supragranular dentate sprouting and to assess the relation between several changes that occur in epileptic tissue with different behavioral manifestations of this experimental model of temporal lobe epilepsy. Pilocarpine-induced status epilepticus (SE) invariably led to cell loss in the hilus of the dentate gyrus (DG) and to spontaneous recurrent seizures. Cell loss was often also noted in the DG and in hippocampal subfields CA1 and CA3. The seizures began to appear at a mean of 15 days after SE induction (silent period), recurred at variable frequencies for each animal, and lasted for as long as the animals were allowed to survive (325 days). The granule cell layer of the DG was dispersed in epileptic animals, and neo-Timm stains showed supra- and intragranular mossy fiber sprouting. Supragranular mossy fiber sprouting and dentate granule cell dispersion began to appear early after SE (as early as 4 and 9 days, respectively) and reached a plateau by 100 days. Animals with a greater degree of cell loss in hippocampal field CA3 showed later onset of chronic epilepsy (r = 0.83, p < 0.0005), suggesting that CA3 represents one of the routes for seizure spread. These results demonstrate that the pilocarpine model of chronic seizures replicates several of the features of human temporal lobe epilepsy (hippocampal cell loss, supra- and intragranular mossy fiber sprouting, dentate granule cell dispersion, spontaneous recurrent seizures) and that it may be a useful model for studying this human condition. The results also suggest that even though a certain amount of cell loss in specific areas may be essential for chronic seizures to occur, excessive cell loss may hinder epileptogenesis.
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PMID:Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. 769 49

Lowering of extracellular Mg2+ results in various forms of epileptiform activity in different parts of temporal lobe slices [5,22] which contain neocortical areas such as areas Te2 or Te3, the entorhinal cortex (EC), subiculum, hippocampal areas CA1 to CA3 and the dentate gyrus [5,11]. In the EC, the subiculum and Te2/Te3 seizure-like events (SLEs) with tonic and clonic electrographic discharge patterns, negative slow field potentials and ionic changes comparable to those during tonic-clonic seizures in intact animals were observed. After 30 to 120 min of recurrent seizure activity (80 +/- 37 min) the seizure-like events (SLEs) developed into a state of late recurrent discharges (LRDs). Since previous studies had shown that the LRDs do not respond to valproic acid in contrast to a blocking effect of this drug on SLEs, we investigated the effects of the clinically employed anticonvulsants phenytoin, carbamazepine, phenobarbital, midazolam and ethosuximide on LRDs. All these agents were unable to block the LRDs in the EC, subiculum and Te2/Te3. This was found true both for concentrations which can block SLEs and for higher concentrations. Thus we conclude that this activity may represent a model of difficult to treat status epilepticus.
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PMID:Paroxysmal epileptiform discharges in temporal lobe slices after prolonged exposure to low magnesium are resistant to clinically used anticonvulsants. 775 May 6

To investigate whether aggravation of damage in hyperglycemic subjects is a continuous function of changes in intra- and extracellular pH during ischemia or whether there is a threshold value, preischemic plasma glucose was varied from 8.3-20.0 mM. 10 min forebrain ischemia was induced. The results showed that no animal with plasma glucose of < 13 mM developed seizures, and that all animals with glucose of > 16 mM died in status epilepticus. Half of the animals with plasma glucose in the range of 13-16 mM showed seizures and 50% of these died. In surviving animals, histological brain damage occurred in the hippocampal CA3 sector, cingulate cortex, thalamic nuclei and substantia nigra, structures normally not injured by 10 min ischemia. The data demonstrate that there is a glucose threshold of 10-13 mM, above which seizures develop and additional damage appears, and another one (> 16 mM), above which seizures are invariably fatal.
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PMID:The influence of plasma glucose concentrations on ischemic brain damage is a threshold function. 782 84

Systemic administration of the cholinergic agonist pilocarpine (350-400 mg/kg, i.p.) to rats induces acute behavioral and EEG status epilepticus followed by apparent complete neurological recovery. In rats receiving higher doses of pilocarpine (i.e., 380-400 mg/kg), recurrent seizures reappear 2-2.5 weeks later and continue to occur as long as the rats are kept alive. Stereological estimates of neurons in regions CA1, CA3 and the dentate granule cell layer in the dorsal hippocampus show a dose-dependent neuronal loss in the CA3 and CA1 subregions. The granule cell layer of the dentate gyrus is not affected. No progressive neuronal loss was observed in the regions studied after 3, 6 and 12 weeks during which the animals displayed spontaneous recurrent seizures. The temporal profile of the epileptic condition induced by pilocarpine and the resulting pattern of neuronal loss in the rat hippocampus are similar to those seen in many cases of human temporal lobe epilepsy. The neuronal loss is dose-dependent and primarily results from the acute pilocarpine-induced seizures as chronic seizures do not produce any measurable additional cell loss in the regions examined in the experimental model used in this study.
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PMID:Quantitative evaluation of neuronal loss in the dorsal hippocampus in rats with long-term pilocarpine seizures. 801 46

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 kynurenine pathway metabolites quinolinic acid and kynurenic acid have been hypothetically linked to the occurrence of seizure phenomena. The present immunohistochemical study reports the activation of astrocytes containing three enzymes responsible for the metabolism of quinolinic acid and kynurenic acid in a rat model of chronic epilepsy. Rats received 90 min of patterned electrical stimulation through a bipolar electrode stereotaxically positioned in one hippocampus. This treatment induces non-convulsive limbic status epilepticus that leads to chronic, spontaneous, recurrent seizures. One month after the status epilepticus, the rats showed neuronal loss and gliosis in the piriform cortex, thalamus, and hippocampus, particularly on the side contralateral to the stimulation. Astrocytes containing the kynurenic acid biosynthetic enzyme (kynurenine aminotransferase) and the enzymes for the biosynthesis and degradation of quinolinic acid (3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase, respectively) became highly hypertrophied in brain areas where neurodegeneration occurred. Detailed qualitative and quantitative analyses were performed in the hippocampus. In CA1 and CA3 regions, the immunostained surface area of reactive astrocytes increased up to five-fold as compared to controls. Enlarged cells containing the three enzymes were mainly observed in the stratum radiatum, whereas the stratum pyramidale, in which neuronal somata degenerated, showed relatively fewer reactive glial cells. Hypertrophied kynurenine aminotransferase- and 3-hydroxyanthranilic acid oxygenase-immunoreactive cells were comparable in their morphology and distribution pattern. In contrast, reactive quinolinic acid phosphoribosyl transferase-positive glial cells displayed diversified sizes and shapes. Some very large quinolinic acid phosphoribosyl transferase-immunoreactive cells were noticed in the molecular layer of the dentate gyrus. In the hippocampus, the number of immunoreactive glial cells increased in parallel to the hypertrophic responses. In addition, pronounced increases in immunoreactivities, associated with hypertrophied astrocytes, occurred around lesioned sites in the thalamus and piriform cortex. These findings indicate that kynurenine metabolites derived from glial cells may play a role in chronic epileptogenesis.
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PMID:Kynurenine pathway enzymes in a rat model of chronic epilepsy: immunohistochemical study of activated glial cells. 823 7

The hsp70 gene is induced by denatured protein in injured cells and is an extremely sensitive and reliable marker of cells injured by ischemia, seizures, and toxins. Normal brains have little detectable hsp70 mRNA or HSP70 protein. After status epilepticus produced by systemic injections of kainic acid, however, HSP70 protein is induced in neurons but not glia in brain regions known to be injured by kainic acid. Global and focal ischemia also induce the hsp70 gene in brain. The induction of HSP70 protein in hippocampus following increasing durations of global ischemia correlates with the regional and cellular vulnerability to ischemia: CA1 neurons express HSP70 after the briefest periods of ischemia followed by CA4, CA3, dentate granule neurons, glia, and lastly, endothelial cells. Moreover, as the severity of ischemia worsens, a transcriptional and/or translational blockade of the hsp70 gene occurs in the same order so that moderate degrees of ischemia induce HSP70 in CA3 neurons and dentate granule neurons but not necrotic CA1 neurons, and severe ischemia induces HSP70 in capillary endothelial cells of hippocampus but not in any infarcted neurons or glia throughout the hippocampus. Brief periods of focal ischemia induce HSP70 primarily in neurons, suggesting that even focal ischemia can produce selective neuronal injury without infarction. In some instances, HSP70 immunoreactive astrocytes surround the HSP70 immunostained neurons. Focal ischemia that produces infarction induces HSP70 primarily in endothelial cells of cerebral blood vessels in the regions of infarction and in neurons and astrocytes on the perimeter or the penumbral area of infarction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HSP70 heat shock gene regulation during ischemia. 824 24

We studied a rat model of chronic epilepsy that shares key features with certain patients with temporal lobe epilepsy. This model relies on a previous period of limbic system status epilepticus established by focal stimulation to one hippocampus. Animals were examined 1 month after recovery from such status epilepticus and compared to unstimulated controls and to animals that received stimulation but did not develop status epilepticus. Two experimental procedures were employed to study changes in paired pulse inhibition of population spike (PS) discharges elicited in CA1 pyramidal cells. One procedure (homosynaptic) delivered two identical stimuli to the CA3 region contralateral to the recording site; the other procedure (heterosynaptic) delivered a conditioning stimulus to the ipsilateral angular bundle and a separate test stimulus to the contralateral CA3. For both procedures, influences of stimulus intensities and of interpulse intervals on the potency of paired pulse inhibition were determined. Based on the results, standardized protocols that assayed the maximal amount of paired pulse inhibition were developed. With the homosynaptic protocol, there was one period of inhibition (interpulse intervals up to 300 ms). Animals that previously experienced limbic status epilepticus had markedly less paired pulse inhibition under these conditions than did controls. The stimulated, non-status epilepticus animals were not different from controls. For the heterosynaptic protocol, there were 2 phases of paired pulse inhibition, early (< 50 ms) and late (> 300 ms), separated by a period of paired pulse facilitation. After status epilepticus there were, compared to controls, decreases in both early and late phases of inhibition. The stimulated, non-status epilepticus animals were not different from controls. For the paired pulse facilitation, there was no difference between the animals that experienced status epilepticus and controls. These findings indicate a profound and enduring disturbance of GABA-mediated inhibition in this model. The heterosynaptic paired pulse protocol deals with a number of confounding issues associated with the homosynaptic protocol in this regard. Furthermore, the results suggest the inhibitory disturbance is diffuse, affecting various inhibitory circuits in the hippocampus.
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PMID:Decreased heterosynaptic and homosynaptic paired pulse inhibition in the rat hippocampus as a chronic sequela to limbic status epilepticus. 843 59

1. Combined hippocampal-parahippocampal slices were employed to study the development of complex epileptiform discharges after Schaeffer collateral stimulation in vitro. With repeated stimulation, slices generated several different types of epileptiform discharges, which were temporally linked to the preceding stimulus, and predictable in their progression. The first epileptiform discharge to be elicited by stimulation was a primary afterdischarge, which began immediately after the stimulation train and progressed with repeated stimulation until it had peaked in amplitude and duration by the third to fifth stimulus train. After development of the primary afterdischarge, a secondary afterdischarge began to appear, with a 2- to 5-min latency after the third to sixth stimulation train, and progressed in amplitude and duration with repeated stimulation, sometimes to durations > 30 min. 2. After development of the secondary afterdischarge, 65-70% of rostral slices triggered long-duration, spontaneous self-sustained activity. This activity consisted of repeated spontaneous 3- to 5-min duration ictallike discharges with a short interval (< 15 min between events), lasting for hours in many cases. These discharges were similar to activity seen in depth recordings of patients with complex partial status epilepticus. This cyclic spontaneous epileptiform activity was blocked by diazepam (100 nM to 1 microM), and potentiated by the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV, 50 microM). Analysis of the temporal progression of epileptiform activity through multiple channel extracellular recordings demonstrated that both the interictal and ictal discharges evident during spontaneous recurrent ictal-like status epilepticus (SE) originated at a site distant from the stimulation locus, and then propagated to area CA1. 3. Intracellular recordings from CA3 neurons during spontaneous recurrent ictallike SE activity revealed the cellular correlates of this activity. Recurrent ictallike discharges were initiated at a cellular level by a large depolarization, accompanied by tonic action-potential firing. As the ictal event progressed, the neuron continued to depolarize, and a period of depolarization block ensued, which was terminated by the gradual repolarization of the neuron, with accompanying phasic burst firing. 4. A second variety of long-duration self-sustained activity was also seen in 5-10% of slices. This type of continuous sustained activity was initiated by an increase in duration of the secondary afterdischarge to 30-120 min duration with repeated stimulation. These sustained discharges were also increased in amplitude and frequency by APV (50 microM) and reduced or blocked by the benzodiazepines diazepam or clonazepam (1 microM). Sustained epileptiform discharges seen in vitro were similar to one form of seizure discharges seen in patients with SE in their frequency, duration, in their progression through a similar electrographic series of stages, and their sensitivity to benzodiazepines. 5. Intracellular recordings from CA3 neurons during continuous SE-like discharges revealed large bursts within this area during generation of generalized epileptiform activity. These bursts were coincident with extracellularly recorded population burst activity in CA1, and so were a circuit phenomenon. 6. This physiological and pharmacological correspondence between the multiple types of SE-like activity seen in vitro and in patients with SE suggests that these long-duration limbic discharges seen in slices may constitute a valuable model for study of the seizure discharges of SE. Future studies exploiting the advantages of in vitro preparations may aid in understanding physiological and pharmacological factors important in generation and control of this grave neurological condition.
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PMID:Long-duration self-sustained epileptiform activity in the hippocampal-parahippocampal slice: a model of status epilepticus. 859 94

Somatostatin-, neuropeptide Y-, neurokinin B- and cholecystokinin-containing neurons were investigated in the rat hippocampus in two chronic models of temporal lobe epilepsy, i.e. 30 days after rapid kindling or electrically induced status epilepticus (post-status epilepticus). After rapid kindling, somatostatin immunoreactivity was strongly increased in interneurons and in the outer and middle molecular layer of the dentate gyrus. In four of six post-status epilepticus rats (status epilepticus I rats), somatostatin immunoreactivity was slightly increased in the dorsal but decreased in the ventral dentate gyrus and molecular layer. Somatostatin immunoreactivity decreased in neurons of the dorsal hilus in the two other post-status epilepticus rats investigated, while a complete loss was found in the respective ventral extension (status epilepticus-II rats). These changes were associated with a different extent of neurodegeneration as assessed by Nissl staining. Similarly, neuropeptide Y immunoreactivity was enhanced in neurons of the hilus and in the middle and outer molecular layer of the dentate gyrus in the dorsal hippocampus of rapidly kindled and status epilepticus-I rats. Neuropeptide Y and neurokinin B immunoreactivity was enhanced in the mossy fibers of all post-status epilepticus rats, but not in the rapidly kindled rats. In status epilepticus-II rats, neuropeptide Y-and neurokinin B-positive fibers were also detected in the infrapyramidal region of the stratum oriens of CA3 and in the inner molecular layer of the dentate gyrus in the dorsal and ventral hippocampus respectively, labeling presumably sprouted mossy fibers. Increased staining of neuropeptide Y and neurokinin B was found in the alveus after rapid kindling. Cholecystokinin immunoreactivity was markedly increased in the cerebral cortex, Ammon's horn and the molecular layer of the dentate gyrus in the ventral hippocampus of rapidly kindled and post-status epilepticus rats. The lasting changes in the immunoreactive pattern of various peptides in the hippocampus may reflect functional modifications in the corresponding peptide-containing neurons. These changes may be involved in chronic epileptogenesis, which evolves in response to limbic seizures.
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PMID:Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy. 859 52


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