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)

Animals exposed to kainic acid (KA) induced status epilepticus display a striking pattern of selective neuronal vulnerability in the hippocampus. Neurons in the hilus/CA3 and CA1 subfields appear particularly sensitive whereas dentate gyrus (DG) granule cells are resistant. The molecular basis for this differential susceptibility remains largely unknown. Recently, an involvement of nitric oxide, c-Jun amino-terminal kinases (JNK) and interleukin-1 beta converting enzyme (ICE)-related proteases has been proposed in KA induced neuronal cell death. In the present study, we have determined the regional expression of transcripts for two modulating genes operating in these pathways, i.e., the endogenous protein inhibitor of neuronal nitric oxide synthase (PIN), and a cytoplasmic inhibitor of the JNK signal transduction pathway, designated JNK interacting protein-1 (JIP-1) and of the gene for the apoptosis-executing protease Caspase-3 in KA-treated animals. The expression of PIN and JIP-1 was found significantly upregulated in granule cells of the resistant DG. In contrast, an induction of the ICE-related protease Caspase-3 was observed in vulnerable hippocampal regions, i.e. CA1, CA3 and hilus. These results point towards PIN and JIP-1 as antiapoptotic factors contributing to selective resistance of granule cells, whereas Caspase-3 may be involved in cell death of hippocampal CA1, CA3 and hilar neurons in the kainate epilepsy model.
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PMID:Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. 1010 Dec 44

Previous studies have demonstrated that remacemide and its desglycinyl metabolite, AR-R 2495AA, reduce neuronal damage in animal models of ischemia, subarachnoid hemorrhage, and traumatic brain injury. The aim of the present study was to investigate whether remacemide hydrochloride also alleviates seizure-induced neuronal damage in a model of status epilepticus induced by the stimulation of the perforant pathway (PP) in the rat. Chronic oral remacemide treatment (3 x 25 mg/kg/day) was started either 2 days before or 2 h after the beginning of PP stimulation (2 mA, 20 Hz, 0.1 ms pulse duration for 60 min). The effects of remacemide treatment on the severity of seizures, electroencephalogram (EEG) parameters, seizure-induced neuronal damage in the temporal lobe regions, and memory impairment were compared to unstimulated and stimulated vehicle-treated controls, and carbamazepine-pre-treated (3 x 40 mg/kg/day) rats. Both remacemide and carbamazepine pretreatments, but not remacemide posttreatment, decreased pyramidal cell damage in the CA3 and CA1 subregions of the hippocampus (P < 0.05). In addition, overall neuronal damage in the extrahippocampal temporal lobe regions (the piriform cortex, entorhinal cortex, and the amygdaloid complex) was milder in remacemide-pretreated rats compared to stimulated control rats (P < 0.01). The neuroprotective effect was most evident on the side contralateral to stimulation. Remacemide or carbamazepine pretreatment had no evident effect on the number or duration of behavioral seizures during PP stimulation. Neither drug altered the spectral parameters of the baseline EEG or prevented status epilepticus-induced EEG slowing observed 2 weeks after PP stimulation. Nor did remacemide or carbamazepine treatment alleviate spatial memory impairment determined in a Morris water-maze task 2 weeks after PP stimulation. Our data provide evidence that pretreatment with remacemide has a moderate neuroprotective effect against status epilepticus-induced neuronal damage.
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PMID:Neuroprotective effect of remacemide hydrochloride in a perforant pathway stimulation model of status epilepticus in the rat. 1021 40

The distribution and time course of changes of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positivity were studied in immature rats (12 and 25 days old) surviving motor status epilepticus (SE) induced by a high dose of pilocarpine. Motor SE characterized by continuous convulsions was interrupted after 2 h by an injection of clonazepam (0.5 mg/kg or 1 mg/kg in 12- and 25-day-old rats, respectively) in order to reduce mortality. Correlation between electroencephalographic and behavioral seizure activity was confirmed using animals with electrodes implanted bilaterally in the hippocampus and sensorimotor cortex. Brains were examined 2, 6, 13, and 21 days after motor SE using NADPH-diaphorase histochemistry. Two types of changes were found in both age groups: (a) decrease of NADPH-d positivity occurred in both neuropil and cell bodies in piriform, periamygdalar, and entorhinal cortices; and (b) NADPH-d positivity was induced in the cell bodies in the hippocampal fields CA1/2, CA3, and dentate gyrus. These changes were more intense in animals surviving SE at postnatal day 25 than in younger age group, and they peaked 2 days after SE. The changes observed after SE disappeared quickly in 12-day-old rat pups, where only moderate changes could be observed in piriform, periamygdalar, and entorhinal cortices 6 days after SE, whereas the changes in the histochemical positivity persisted in older animals even 21 days after SE.
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PMID:Changes in NADPH-diaphorase positivity induced by status epilepticus in allocortical structures of the immature rat brain. 1021 Jan 66

Substance P (SP), a member of the tachykinin family, is widely distributed in the central nervous system and is involved in a variety of physiological processes including cardiovascular function, inflammatory responses, and nociception. We show here that intrahippocampal administration of SP triggers self-sustaining status epilepticus (SSSE) in response to stimulation of the perforant path for periods too brief to have any effect in control rats, and this SSSE generates a pattern of acute hippocampal damage resembling that known to occur in human epilepsy. The SP receptor (SPR) antagonists, spantide II and RP-67,580, block both the initiation of SSSE and SSSE-induced hippocampal damage and terminate established anticonvulsant-resistant SSSE. SSSE results in a rapid and dramatic increase in the expression of preprotachykinin A (a precursor of SP) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus as well as in hippocampal mossy fibers. SP also increases glutamate release from hippocampal slices. Enhanced expression of SP during SSSE may modulate hippocampal excitability and contribute to the maintenance of SSSE. Thus, SPR antagonists may constitute a novel category of drugs in antiepileptic therapy.
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PMID:Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. 1022 Apr 58

There has been direct evidence of gamma-aminobutyric acidA receptor modification during status epilepticus. Neuropeptides galanin and neuropeptide Y were demonstrated to play a role in terminating status epilepticus. Many of the CA3 pyramidal neurons destined to die as a consequence of status epilepticus were demonstrated to diminish expression of the GluR2 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors. It was demonstrated that the pattern of cell loss due to status epilepticus is distinct in immature pups compared with adult rats. The genetic basis for susceptibility to neuronal loss during status epilepticus was described. There was increasing evidence of unique receptors and ion channels in the epileptic brain. The molecular studies of epileptic gamma-aminobutyric acidA receptors present on dentate granule cells of rats with temporal lobe epilepsy revealed altered gene and receptor expression before onset of recurrent spontaneous seizures. They also revealed insertion of new gamma-aminobutyric acidA receptors in the inhibitory synapses present on soma and proximal dendrites of dentate granule cells.
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PMID:Status epilepticus in epileptogenesis. 1022 52

Although the immature brain is highly susceptible to seizures, it is more resistant to seizure-induced neuronal loss than the adult brain. The developing brain contains high levels of neurotrophins which are involved in growth, differentiation and survival of neurons. To test the hypothesis that neurotrophins may protect the developing brain from seizure-induced neuronal loss, brain-derived neurotrophic factor up-regulation was blocked by intracerebroventricular infusion of an 18mer antisense oligodeoxynucleotide sequence to brain-derived neurotrophic factor in 19-day-old rats using micro-osmotic pumps. Control rats were infused with sense or missense oligodeoxynucleotide. Status epilepticus was induced by intraperitoneal administration of kainic acid 24 h after the start of oligodeoxynucleotide infusion. Seizure duration was significantly increased in the antisense oligodeoxynucleotide plus kainic acid group compared to groups that received kainic acid alone or kainic acid plus sense or missense oligodeoxynucleotide. There was no difference between groups in the latency to forelimb clonus. A twofold increase in brain-derived neurotrophic factor levels was observed in the hippocampus 20 h following kainic acid-induced seizures. This kainic acid-induced increase was absent in animals receiving infusion of antisense oligodeoxynucleotide to brain-derived neurotrophic factor at time of seizure induction. Hippocampi of rats in this group (antisense oligodeoxynucleotide plus kainic acid) showed a loss of CA1 and CA3 pyramidal cells and hilar interneurons. This neuronal loss was not dependent upon seizure duration since animals injected with diazepam to control seizure activity in the antisense plus kainic acid group also showed similar neuronal loss. Administration of kainic acid or infusion of antisense alone did not produce any cell loss in these regions. Induction of seizures at postnatal day 20, in the presence or absence of antisense oligonucleotide, did not produce an impairment in learning and memory when tested 15 days later in the Morris water maze. The hippocampi of these animals did not show any synaptic reorganization as assessed by growth-associated protein-43 immunostaining and Timm staining. Our findings confirm prior studies demonstrating that seizures in the immature brain are associated with little, if any, cell loss. However, when seizure-induced increase in brain-derived neurotrophic factor is blocked, seizures do result in neuronal loss in the developing brain. Thus, brain-derived neurotrophic factor appears to provide protection against kainic acid seizure-induced neuronal damage in the developing brain.
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PMID:Neuroprotective effects of brain-derived neurotrophic factor in seizures during development. 1033 79

Neuronal damage in relation to the duration of seizure was studied in limbic status epilepticus (SE) induced by electric stimulation of naive rats. Adult Sprague-Dawley rats were stimulated at the right amygdala to induce SE. To stop the seizures, diazepam was given to different groups of rats at 0.5 h (n = 4), 1 h (n = 6), 2 h (n = 6), and 3-4 h (n = 8) of SE. Eighteen hours after the end of SE, the rats were perfusion fixed. Naive (n = 6) and sham-operated (n = 4) rats served as controls. Horizontal paraffin sections were stained with acid fuchsin and cresyl violet. Neuronal damage was absent after 30 min of SE. Status epilepticus of 1 h or longer duration regularly caused neuronal damage to the cerebral cortex, thalamus, hippocampus, amygdala, and pars reticulata of the substantia nigra. Damage in the cerebral cortex predominated in the entorhinal, temporal, and pyriform regions. In the hippocampus, the dentate hilus was most severely affected, followed by CA3 and CA1. Damage to the dentate granule layer was mild. Further studies of the pathophysiology of excitotoxicity may help to protect patients from sequels of status epilepticus such as neuronal damage and epilepsy.
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PMID:Neuropathology of limbic status epilepticus induced by electrical stimulation of naive rats. 1040 13

Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of gamma-aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABA(A) receptors in chronically epileptic animals. In addition, the pharmacological properties of GABA(A) receptors in post-SE epileptic animals are quite different compared to controls. In particular, GABA(A) receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of alpha1 subunits of the GABA(A) receptor relative to other alpha subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc-containing "sprouted" mossy fiber terminals innervating the proximal dendrites of DGCs in the post-SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block "epileptic" zinc-sensitive GABA(A) receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post-SE epileptic limbic system.
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PMID:Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. 1042 58

It is well documented that prolonged seizures (status epilepticus) can cause neuronal injury and result in synaptic reorganization in certain brain regions. However, the effect of recurrent, relatively short seizures in young animals on subsequent brain development is not known. To study the consequences of recurrent seizures on the developing brain, we subjected immature rats to a total of 50 flurothyl-induced seizures from postnatal day 11 until day 23. Immunohistochemistry for c-fos was performed to characterize the pattern of neuronal activation following the seizures. Cell counting of dentate granule cells, CA3, CA1, and hilar neurons, using unbiased stereological methods, and the silver impregnation method were used to evaluate neuronal death following the recurrent seizures. Timm and Golgi staining were performed four weeks after the 50th seizure to evaluate the effects of recurrent seizures on synaptic organization. Our results show that recurrent flurothyl-induced seizures progressively increased excitability of the brain, as revealed by a dramatic increase in the extent and intensity of c-fos immunostaining. While no cell loss was detected in the hippocampus with either Cresyl Violet or silver stains, animals experiencing multiple daily seizures developed increased mossy fiber sprouting in both the supragranular layer of the dentate gyrus and the infrapyramidale layer of the CA3 region. Golgi staining confirmed that there was an increase in mossy fibers in the pyramidal cell layer. Our results suggest that serial recurrent seizures in the immature brain can lead to significant changes in mossy fiber distribution even though the seizures do not cause significant hippocampal cell loss.
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PMID:Consequences of recurrent seizures during early brain development. 1042 98

Prolonged seizures are associated with injury to vulnerable neurons, particularly in the hippocampus. Identification of compounds that attenuate injury after prolonged seizures could be of value in the management of refractory status epilepticus. We hypothesized that topiramate, an anticonvulsant with multiple mechanisms of action, would attenuate hippocampal neuronal injury when given after experimental status epilepticus. Limbic status epilepticus was induced in adult male Wistar rats for 140 min by unilateral hippocampal electrical stimulation. Rats then received intraperitoneal injections of either vehicle (n=6) or topiramate at 20 mg/kg (n=6), 40 mg/kg (n=7) or 80 mg/kg (n=7). Three days later, hippocampal sections were processed for neuronal degeneration using a silver impregnation stain. Seizure-induced damage was assessed by measuring the density of silver staining in hippocampal regions CA1, CA3 and dentate hilus. Administration of topiramate at each dose was associated with a significant reduction in staining density bilaterally in area CA1 and the dentate hilus. Reduction in staining density in area CA3 was seen contralateral to the side of stimulation at the two higher topiramate doses only. The results indicate that administration of topiramate after experimental status epilepticus can attenuate seizure-induced hippocampal neuronal injury.
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PMID:Topiramate reduces neuronal injury after experimental status epilepticus. 1043 11


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