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)

Autopsy study of a patient who died after an episode of prolonged unilateral status epilepticus revealed neuronal loss in the hippocampus on the epileptic side, with gliosis confined to the CA1 and CA3 fields. There was loss of the parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)-ergic interneurons in the hippocampus on that side. There was also loss of the normal laminar pattern of substance P staining with increased substance P immunoreactivity in the supragranular plexus on that side. Met-enkephalin immunoreactivity was also increased in the outer molecular layer of the dentate gyrus on the epileptic side. Mossy fibers on the epileptic side stained more strongly with the Hicks' silver stain and with antibodies against glutamate and taurine, but less intensely with antibodies against calbindin. In the contralateral cerebellum, there was Purkinje cell loss, injury to the remaining Purkinje cells, and increased prominence of the Bergmann glia. Our observations show that prolonged unilateral seizure activity can be associated with specific histochemical changes in the human hippocampus.
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PMID:Neuropathologic asymmetries in the brain of a patient with a unilateral status epilepticus. 171 86

Benzodiazepines are the most potent drugs used in the management of status epilepticus (SE). A number of presynaptic, postsynaptic, and nonsynaptic actions of benzodiazepines have been described. However, only the benzodiazepines' enhancement of gamma-aminobutyric acid (GABA)ergic inhibition and their reduction of repetitive firing occur at concentrations of unbound drug comparable to those that block absence seizures or stop clinical SE in patients. Thus, it is likely that these actions contribute to antiepileptic and anti-SE efficacy of the benzodiazepines. A predictable sequence of progressive electroencephalographic (EEG) changes during the course of generalized convulsive SE, both in humans and in experimental models, has been recently described. The homology of the sequence of EEG patterns in patients and in experimental models supports the concept that animal models should be useful in evaluating the treatment of clinical SE, and benzodiazepines are effective in stopping SE in a number of animal models. Late SE in animals, however, as in humans, is less responsive to treatment than is early SE. Forty-seven clinical studies in which clonazepam, diazepam, or lorazepam was used in the treatment of SE have been reported. Overall, lasting control of SE was achieved in 79% of the 1,346 patients in these noncontrolled studies. However, no data yet exist to differentiate the efficacy of 1 of the benzodiazepines from that of the others. Therefore, the choice of benzodiazepine is best determined by availability and by pharmacokinetic differences. Because of a much smaller volume of distribution of unbound drug, lorazepam appears to have a significantly longer effective duration of action against SE than does diazepam, which is rapidly redistributed to lipid stores in the body after intravenous administration. For this reason, we now use lorazepam in the initial treatment of patients with generalized convulsive SE.
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PMID:The role of benzodiazepines in the management of status epilepticus. 215 32

The effects of clinically used anticonvulsant drugs on high-frequency sustained repetitive firing (SRF) of action potentials and on postsynaptic responses to iontophoretically applied gamma-aminobutyric acid (GABA) have been compared to establish a classification of anticonvulsant drugs based on cellular mechanisms of action. By using concentrations in the range of therapeutic cerebrospinal fluid values in humans, drugs have been separated into three categories: Phenytoin, carbamazepine, and valproic acid limited SRF, but did not alter GABA responses. Phenobarbital, clonazepam, and diazepam augmented GABA responses and limited SRF only at concentrations above the therapeutic range in ambulatory patients but that are achieved in the acute treatment of status epilepticus. Ethosuximide failed to affect SRF or GABA responses even at supratherapeutic concentrations. Ability of an anticonvulsant to limit SRF correlated well with efficacy against generalized tonic-clonic seizures clinically and against maximal electroshock seizures in experimental animals. Augmentation of GABA responses and lack of limitation of SRF correlated with efficacy against generalized absence seizures in humans and against pentylenetetrazol-induced seizures in animals. However, ethosuximide must act against generalized absence seizures and against pentylenetetrazol-induced seizures by a third, as yet unknown, mechanism. Other actions occurring at supratherapeutic concentrations correlated with clinical toxicity.
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PMID:Anticonvulsant drug mechanisms of action. 240 25

The occurrence of seizure activity in human temporal lobe epilepsy or status epilepticus is often associated with a characteristic pattern of cell loss in the hippocampus. An experimental model that replicates this pattern of damage in normal animals by electrical stimulation of the afferent pathway to the hippocampus was developed to study changes in structure and function that occur as a result of repetitive seizures. Hippocampal granule cell seizure activity caused a persistent loss of recurrent inhibition and irreversibly damaged adjacent interneurons. Immunocytochemical staining revealed unexpectedly that gamma-aminobutyric acid (GABA)-containing neurons, thought to mediate inhibition in this region and predicted to be damaged by seizures, had survived. In contrast, there was a nearly complete loss of adjacent somatostatin-containing interneurons and mossy cells that may normally activate inhibitory neurons. These results suggest that the seizure-induced loss of a basket cell-activating system, rather than a loss of inhibitory basket cells themselves, may cause disinhibition and thereby play a role in the pathophysiology and pathology of the epileptic state.
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PMID:Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. 287 52

We induced generalized seizures by cortical injection of penicillin in anesthetized, paralyzed cats. After they had developed recurrent ictal-interictal ECoG cycling and fictive tonic-clonic motor convulsions (status epilepticus), we studied the effect of systemically administered neuropharmacological agents on the seizure cycling. Antagonists of adenosine receptors, theophylline and 8-cyclopentyltheophylline, increased the cycle period due to marked prolongation of duration of ictal discharge, often to more than 30 min. Dipyridamole, an inhibitor of adenosine reuptake, lengthened the interictal phase of the seizure with no effect on ictal duration. Antagonists of gamma-aminobutyric acid and opioid peptides had no effect on either ictal or interictal phases nor did the nonspecific neural excitant, doxapram. These findings suggest that a major mechanism of ictal-interictal cycling during status epilepticus is the alternating accumulation during the ictal phase and clearance during the interictal phase of the inhibitory neurochemical, adenosine.
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PMID:Role of endogenous adenosine in recurrent generalized seizures. 291 62

The effects of progabide, a direct gamma-aminobutyric acid (GABA) receptor agonist, on bicuculline-induced seizures have been tested in developing rats, ages 7-28 days, to study the correlation between the antiepileptic effectiveness of this drug and the level of functional maturation of the GABAergic system. The incidence, latency of appearance, and behavioral characteristics of the epileptic manifestations, their evolution toward status epilepticus, and the percentage of recovery from status epilepticus have been evaluated in rats that had received a single injection (treatment) or three successive daily administrations (pretreatment) of progabide. The results have been compared with those obtained in a control group of animals in which only bicuculline had been injected. In rats ages 7-14 days the treatment appears to be substantially ineffective in protecting animals against bicuculline seizures and their consequences, probably because of the substantial immaturity of the GABAergic system at birth and during the first days of life. At this age, repetitive administrations of progabide cause a protective anticonvulsant action more remarkable than the single injection, particularly when using the higher doses of the substance. In 15-28-day-old rats, the treatment significantly reduces the lethality from status epilepticus but does not substantially modify the incidence of seizures, their latency of appearance, or their evolution toward status epilepticus. As in younger animals, in these rats also pretreatment is more effective than treatment against bicuculline seizures, whatever dose of progabide is used. At this age, therefore, the anticonvulsant properties of progabide appear to be more remarkable than in the previous age, probably because of a higher level of development of the GABAergic system, according to biochemical data on the GABAergic system ontogenesis.
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PMID:Effects of progabide on bicuculline-induced epileptic seizures in developing rats. 321 76

Most of the experimental models of status epilepticus result either from administration of a variety of excitatory neurotoxins or repeated electrical stimulation. Here we propose a new model based on the withdrawal of chronic gamma-aminobutyric acid (GABA) infusion into limbic structures via osmotic minipumps. Appearing with a latency of about 50 min, continuous pseudo-rhythmic EEG epileptic spiking was elicited for about 12-24 h after removal of GABA infusion in hippocampus or amygdala. No apparent distant brain damage was observed. This model differs from many others by several features and could result from different mechanisms.
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PMID:Local asymptomatic status epilepticus induced by withdrawal of GABA infusion into limbic structures. 341 83

Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
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PMID:Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. 370 28

The lumbar cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.
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PMID:GABA levels in cerebrospinal fluid of patients with epilepsy. 393 65

Bicuculline methiodide (0.5-3 nmol) and picrotoxin (0.5-4 nmol) were injected uni- or bilaterally into the rat amygdala and the resulting behavioural, electroencephalographic and morphological alterations were studied. In rats treated unilaterally with lowest doses of either bicuculline or picrotoxin (0.5 and 1 nmol) increase in the locomotor activity, occasional myoclonus of the hindlimbs and wet dog shakes were observed. At doses of 2-3 nmol, both gamma-aminobutyrate antagonists produced a sequence of repetitively occurring behavioural alterations including limbic gustatory automatisms, tremor and myoclonus of the forelimbs, head nodding and rearing, that developed over 15-30 min and built up progressively into the recurrent motor limbic seizures lasting for 1-6 h. In animals injected bilaterally with either bicuculline (0.5-3 nmol) or picrotoxin (0.5-3 nmol) motor limbic seizures rapidly developed into the status epilepticus lasting for several hours. Bicuculline and picrotoxin produced both ictal and interictal epileptiform activity in the electroencephalogram. A spectrum of electroencephalographic changes consisted of high voltage fast activity, slow and fast voltage spiking, paraoxysmal bursts and periods of postictal depression. The earliest electrographic alterations appeared in the amygdala and then rapidly spread to cortical areas. Electrographic seizures started 1-10 min after unilateral injections of large doses of bicuculline and pictrotoxin (2-4 nmol). Ictal periods lasted for 1-2 min, recurred every 5-10 min and were followed by periods of depression of the electrographic activity. Bilateral injections of large doses of both gamma-aminobutyrate antagonists (2-3 nmol) resulted in the status epilepticus. Morphological examination of frontal forebrain sections with light microscopy revealed a widespread damage to the amygdala, olfactory cortex, substantia nigra, thalamus, hippocampus and neocortex. Pretreatment of animals with diazepam prevented the build-up of convulsive activity and brain damage produced by bicuculline or picrotoxin. Muscimol retarded the appearance and shortened the duration of convulsive activity, but did not alter the sequence and intensity of seizures. The results indicate that gamma-aminobutyrate antagonists, bicuculline and picrotoxin when directly applied to the amygdala can elicit in rats motor limbic seizures, epileptic changes in the electroencephalogram indicative of repetitive limbic seizures, and status epilepticus accompanied by seizure-related brain damage.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Injections of picrotoxin and bicuculline into the amygdaloid complex of the rat: an electroencephalographic, behavioural and morphological analysis. 397 84


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