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)

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.
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PMID:Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. 152 53

A pilot case-control quantitative study of the hippocampus in patients with severe status epilepticus was performed to identify specific patterns of pyramidal cell loss. Pyramidal cell densities from five patients who died following status epilepticus were compared with five normal controls and five controls matched for age, hypoxia/ischemia, previous epilepsy, and alcohol abuse. Neuronal densities were greatest in the normal control group and least in patients with status epilepticus. Significant reductions were identified in Sommer's sector (prosubiculum and CA1) as well as in CA3 when compared to normal controls.
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PMID:Hippocampal pyramidal cell loss in human status epilepticus. 173 57

Neuronal necrosis in the brain resulting from status epilepticus of 15 to 120 minutes duration in ventilated and well-oxygenated rats was assessed. Seizures were induced by inhalation of the convulsant gas flurothyl, and terminated by withdrawal of flurothyl and a single injection of thiopental. The animals were allowed to recover for one week, and neuronal damage was assessed by cell counts following subserial sectioning of the brain and microscopical examination of the sections. Infarction of the pars reticulata of the substantia nigra occurred in 5 of the 6 animals with seizure duration of 30 minutes, and in all animals with longer seizure durations. There also was a common affectation of the central parts of the globus pallidus. The pars compacta of the substantia nigra was never affected. After 45 to 120 minutes of seizures, moderate neuronal necrosis was observed in the neocortex (layers 3 and 4), and after 60 to 120 minutes was seen in amygdaloid and thalamic nuclei, as well as in CA4 and CA1 hippocampal pyramidal cells. Notably, CA3 neurons were not damaged nor were dentate granule cells affected. After 120 minutes of seizures, damage regularly affected the neocortex and the ventral-posterior nuclei of the thalamus. A conspicuous feature was the localization of neuronal necrosis at sites close to the ventricles.
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PMID:Status epilepticus in well-oxygenated rats causes neuronal necrosis. 405 57

Neuronal lesions in the brain occur in conditions associated with a reduced supply of oxygen (hypoxia and ischemia) and glucose (hypoglycemia) as well as in those associated with a pathologically enhanced neuronal activity (status epilepticus). In only two of these conditions (hypoxia and ischemia) are the lesions correlated to cellular oxygen lack, and gross energy failure is absent in one condition (status epilepticus). Although anaerobic mechanisms seem responsible for the cell injury in hypoxia and ischemia, oxidative mechanisms could operate in hypoglycemia and status epilepticus. Since the supply of oxygen has not ceased altogether in hypoxia and incomplete ischemia, and since reoxygenation/recirculation leads to a transient increase in tissue oxygen tensions, one cannot exclude the possibility that oxidative mechanisms contribute to the final damage following all types of cellular oxygen lack. We have failed to obtain evidence that peroxidative degradation of cellular constituents occurs in hypoglycemia and status epilepticus. Thus, there is neither a perturbation of the redox state of the glutathione pool of the tissue nor a measurable degradation of polyenoic phospholipid-bound fatty acids. It is emphasized that the cascade of events triggered by an accumulation of free polyenoic fatty acids, mainly arachidonic acid, may contribute to cell lesions by leading to cell edema and/or microcirculatory changes. During seizures, such an accumulation occurs even though energy failure is moderate and it may conceivably contribute to cell damage. In general, though, mechanisms of cell damage in the brain remain partly elusive.
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PMID:Neuronal cell damage in the brain: possible involvement of oxidative mechanisms. 693 2

The cellular and molecular pathophysiology of status epilepticus (SE) provides a conceptual framework for understanding clinical scenarios and prospectively designing logical therapies. SE is a dynamic process that evolves over time in a predictable manner with an established sequence of EEG, motor, physiologic, and cellular changes. Neuronal injury and death are the result of processes intrinsic to the brain, mediated by a complex neurotoxic cascade consisting of multiple serial and parallel processes. The risk of cell injury depends also on the overall pathophysiologic profile, including the presence of alterations resulting from SE and occurring independent of SE. On neurophysiologic grounds, we divide SE into "spike-wave" and "nonspike-wave" forms. Spike-wave "absence" status epilepticus carries a low risk of epileptic brain damage, and therapy should be adjusted accordingly. All nonspike-wave SE has a theoretical basis for epileptic brain damage, but the actual risk is variable. There is a significant known risk of cell injury during generalized convulsive SE, a variety of nonspike-wave SE, so aggressive treatment is warranted to prevent sequelae. There is also a theoretical basis for epileptic brain damage in nonspike-wave nonconvulsive SE, but prospective studies are needed to determine which of these patients warrant aggressive therapy. Based on pathophysiologic principles, future treatment of nonspike-wave SE may use a combination of anti-ictal agents, including gamma-aminobutyric acid agonists and N-methyl-D-aspartate antagonists, as well as various neuroprotectants.
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PMID:Pathophysiology of status epilepticus. 756 21

Adenosine is thought to act as an endogenous anticonvulsant and neuroprotective substance in the brain. In the present study we compared neuronal death following status epilepticus (SE) induced in the presence of 8-cyclopentyl-1,3-dimethylxanthine (8-CPT), an A1-adenosine receptor antagonist, with that following SE induced by continuous hippocampal stimulation. Hippocampal damage was characterized using selective nerve and nonnerve cell markers. Six days after SE, both models produced similar patterns of CA1 and CA3 cell loss and selective loss of parvalbumin and hilar somatostatin-immunoreactive interneurons. Calbindin D28K-immunoreactive interneuron numbers and calbindin D28K immunoreactivity in dentate granule cells remained unchanged although calbindin D28K staining was lost in damaged CA1 neurons. Neuronal injury in these areas was also accompanied by reactive gliosis and microglial proliferation, as well as the production of basic fibroblast growth factor and insulin-like growth factor-1 by astrocytes. Although hippocampal damage appeared to be more severe after SE induced in the presence of 8-CPT, this may be due to the increased severity of SE generated in this model.
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PMID:Neuronal injury following electrically induced status epilepticus with and without adenosine receptor antagonism. 764 19

We studied the efficacy of the competitive NMDA receptor antagonist CGP 40116 in protecting against seizure-induced neuronal necrosis from lithium-pilocarpine-induced status epilepticus (SE). Rats were given CGP 40116 either before SE (12 mg/kg i.p.) or 15 min after the onset of SE (4, 12 and 24 mg/kg); controls received normal saline 15 min after SE began. Diazepam and phenobarbital were given i.p. after 3 h of SE to stop the seizures. Rats were killed 24 h later, and their brains were processed for light microscopic examination. Neuronal damage occurred in 24 of 25 brain regions examined in saline-injected animals. Protection was maximal in rats given 12 and 24 mg/kg CGP 40116 after SE onset: 19 and 21 of the 24 damaged regions were protected respectively, but the 24 mg/kg group had a mortality rate comparable to saline-injected controls. No necrotic neurons were found in posterior cingulate and retrosplenial neurons at the two highest CGP 40116 doses, suggesting that the transient cytoplasmic vacuolization induced by NMDA receptor antagonists does not progress to frank necrosis. In rats given CGP 40116 seizure discharges were not eliminated, but their amplitudes were significantly reduced 2 h after SE began. The periodic epileptiform discharge (PED) EEG pattern, probably a sign of widespread neuronal damage, developed in saline-injected controls after 2-2.5 h of SE but not in rats given 12 and 24 mg/kg of CGP 40116. CGP 40116 provided widespread protection against seizure-induced neuronal necrosis, suggesting that an essential step in its production is NMDA receptor activation by endogenous glutamate. The neuroprotection provided was not simply an antiepileptic effect, since electrographic seizures persisted despite NMDA receptor blockade. CGP 40116 and NMDA receptor antagonists in general could be useful as adjunctive neuroprotectants in patients with refractory SE.
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PMID:The competitive NMDA receptor antagonist CGP 40116 protects against status epilepticus-induced neuronal damage. 791 91

Neuronal loss and gliosis were detected in the rat hippocampus soon after unilateral intra-amygdala injection of kainate (KA) (2.5 nmol) while solid mossy fiber sprouting could be seen only fourteen days after this injection. Using this experimental model, we examined the metabotropic glutamate receptor (mGluR)-induced inositol phosphate (IP) formation in hippocampal synaptoneurosomes and slices. In synaptoneurosomes prepared from ipsilateral hippocampi fourteen days following injection, there were no significant changes in mGluR- and carbachol(CARB)-stimulated IPs syntheses when sham-operated and KA-injected animals were compared. In the corresponding hippocampal slices, significant increases of the mGluR responses mediated by ibotenate (IBO) and aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) were noted after KA application. The net stimulation values respectively expressed in a pair-wise fashion for buffer-injected control and KA-treated animals were IBO: 1,947 +/- 457 and 10,553 +/- 1,242; t-ACPD: 1,557 +/- 662 and 9,449 +/- 2,251 dpm/mg protein respectively. Significantly augmented mGluR responses in hippocampal slices were also measured at 7, 42 and 92 days after KA injection. There were, however, no significant increases in CARB-stimulated phosphoinositide hydrolysis in the hippocampal slices at all time-intervals after KA administration. These findings show that there are differences between the mGluR responses in hippocampal synaptoneurosome and slice preparations, suggesting the presence of two distinct populations of mGluR in each of these two models. The large specific increases in certain mGluR activities after KA-induced status epilepticus in hippocampal slices could represent one of the molecular mechanisms which underlie the profound morphological changes, in particular gliosis or mossy fiber sprouting, which follow the KA-induced status epilepticus.
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PMID:Kainate-induced status epilepticus leads to a delayed increase in various specific glutamate metabotropic receptor responses in the hippocampus. 806 81

In an effort to validate methods to be used in a screen for drugs effective as anticonvulsants for soman-induced convulsions, scopolamine (0.2 mg/kg) or diazepam (1 mg/kg) were given (i.m.) to male guinea pigs as a pretreatment 30 min before a convulsant dose of soman. Pyridostigmine, atropine and pralidoxime chloride also were given to counteract the lethality of soman. All animals challenged with soman and which did not receive either diazepam or scopolamine exhibited convulsive status epilepticus (SE), identified by continuous electrographic seizure activity (EGSA) and continuous motor convulsions. Despite the presence of continuous motor convulsions in all animals pretreated with diazepam and challenged with soman, EGSA was not observed in five of the seven animals. Continuous motor convulsions developed in four of seven animals pretreated with scopolamine and challenged with soman, but EGSA was not observed in any scopolamine-pretreated guinea pig. Neuronal necrosis was observed in the hippocampus, thalamus, amygdala, and cerebral and pyriform cortices in each animal with EGSA, but not brain damage was found in subjects without EGSA. Thus, although convulsions, EGSA and brain damage normally occur together in animals exposed to soman, the convulsions can be pharmacologically dissociated from the EGSA and brain damage, demonstrating that the clinically manifested convulsions are not dependent on EGSA recorded from the cortex or on abnormal activity which leads to neuronal necrosis in the forebrain.
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PMID:Pharmacological dissociation of the motor and electrical aspects of convulsive status epilepticus induced by the cholinesterase inhibitor soman. 845 54

The temporal evolution of irreversible neuronal damage from pilocarpine-induced seizures was studied by light microscopy. Neuronal cell death was judged on a 0-3 scale by estimating the percentage of acidophilic neurons in each of 23 brain regions. In addition, in the dorsal dentate hilus (CA4), quantitative cell counts of normal and acidophilic neurons were also performed. A few dead neurons (grade 0.5 damage) appeared in ventral hippocampal CA1 and CA3 regions after 20-min status epilepticus (SE). Slight-to-mild damage (grades 0.5-1.5) occurred in 14 and 12 brain regions after 40-min and 1-h SE respectively, and slight-to-moderate damage (grades 0.5-2.0) was found in 15 regions after 3-h SE. Twenty-four h and 72 h after 3-h SE, there was slight-to-severe damage (grade 0.5-3.0) in 22 and 21 regions respectively. Three-h SE produced more severe damage to 7 brain regions compared to 1-h SE, and 16 regions had more pronounced neuronal injury 24 h after rather than 0-4 h after 3-h SE. Eight brain regions had less damage 72 h compared to 24 h after SE, probably because of progressive neuronal lysis and dropout, but in mediodorsal and lateroposterior thalamic nuclei damage worsened from 24 to 72 h after SE. Neuronal cell counting revealed 20% acidophilic neurons in dorsal dentate hilus after 40-min SE and no difference between the 1-h and 3-h seizure groups (31% vs. 43% acidophilic neurons respectively). Among the 3 groups of rats with 3-h SE and varying recovery periods, the 24-h and 72-h recovery groups had higher percentages of acidophilic neurons (65% and 54% respectively) than the 0-4-h group (43%). Finally, the hippocampal CA2 region and dentate granule cell layer and the caudate-putamen, considered resistant to seizure-induced cell injury, were all damaged from SE lasting 40 min or more.
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PMID:The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. 882 81


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