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)

Permanent cognitive impairment is common following status epilepticus (SE) in both humans and animals. We examined the effect of the NMDA antagonist ketamine administered after SE onset on two forms of associative learning in the rat: conditioned taste aversion and fear-conditioned analgesia. Following the onset of lithium/pilocarpine-induced SE, rats were administered either ketamine (100 mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked deficits in both learning measures at 1 month after SE. In contrast, ketamine-treated and nonepileptic control animals did not differ in performance for either task. Although studies have shown that ketamine is ineffective at controlling electrographic seizures early in SE, these results are consistent with previous studies showing that ketamine can preserve learning proficiency if administered shortly after seizure onset. As a clinically available drug, ketamine may prove useful in the treatment of SE when combined with conventional antiepileptic strategies.
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PMID:Ketamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset. 1260 94

Systemic administration of kainic acid in C57BL/6 and FVB/N mice induces a comparable level of seizure induction yet results in differential susceptibility to seizure-induced cell death. While kainate administration causes severe hippocampal damage in mice of the FVB/N strain, C57BL/6 mice display no demonstrable cell loss or damage. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. As glutamate receptors are thought to participate in seizure induction and the subsequent neuronal degeneration that ensues, previous studies have proposed that variation in the precise subunit composition of glutamate receptors may result in differential susceptibility to excitotoxic cell death. Thus, we chose to examine the relationship between the cellular distribution and expression of glutamate receptor subunit proteins and cell loss within the hippocampus in mouse strains resistant and susceptible to kainate-induced excitotoxicity. Using semi-quantitative Western blot techniques and immunohistochemistry with the use of antibodies that recognize subunits of the KA (GluR5,6,7), AMPA (GluR1, GluR2, and GluR4), and NMDA (NMDAR1 and NMDAR2A/2B) receptors, we found no significant strain-dependent differences in the expression or distribution of these glutamate receptor subunits in the intact hippocampus. Following kainate administration, expression changes in ionotropic glutamate receptor subunits paralleled the development of susceptibility to cell death in the FVB/N strain only. Strain differences in hippocampal vulnerability to kainate-induced status epilepticus are not due to glutamate receptor protein expression.
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PMID:Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. 1267 Jul 4

Various studies demonstrated that the neurotransmitter norepinephrine (NE) plays a relevant role in modulating seizures; in particular, a powerful effect consists in delaying the kindling of limbic areas such as the amygdala and hippocampus. Given the rich NE innervation of limbic regions, we selected a sensitive trigger area, the anterior piriform cortex, to test whether previous loss of noradrenergic terminals modifies sporadic seizures in rats. The damage to locus coeruleus terminals was produced by using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 60 mg/kg i.p.). In intact rats, bicuculline (a GABA-A antagonist, 118 pmol) microinfused into this area produced sporadic seizures, while in rats previously injected with DSP-4, bicuculline determined long-lasting self-sustaining status epilepticus. In intact rats, sporadic seizures were accompanied by a marked increase in norepinephrine release in the contralateral piriform cortex, while in locus coeruleus-lesioned rats this phenomenon was attenuated. While bicuculline-induced sporadic seizures were prevented by the focal infusion of amino-7-phosphonoheptanoic acid (AP-7, a selective NMDA antagonist), or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide (NBQX, a selective non-NMDA antagonist), status epilepticus obtained in norepinephrine-lesioned rats was insensitive to AP-7 but was still inhibited by NBQX. By using fluorescent staining for damaged (Fluoro-Jade B) and intact (DAPI) neurons, as well as cresyl violet, we found that rats undergoing status epilepticus developed neuronal loss in various limbic regions. This study demonstrates a powerful effect of noradrenergic terminals in regulating the onset of limbic status epilepticus and its sensitivity to specific glutamate antagonists.
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PMID:A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus. 1282 66

In children, non-convulsive status epilepticus (NCSE) is rare and difficult to treat. Response to steroids and GABAergic medication is variable and often decreases with increasing duration of NCSE. We present our experience with oral ketamine, an NMDA-receptor antagonist, administered to five children with severe epilepsy (Lennox-Gastaut Syndrome, myoclonic-astatic epilepsy, progressive myoclonic epilepsy and Pseudo-Lennox Syndrome) during an episode of NCSE. Resolution of NCSE was documented in all cases clinically and electroencephalographically within 24-48 hours of starting ketamine. No significant side effects were noted.
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PMID:Oral ketamine in paediatric non-convulsive status epilepticus. 1296 77

The relationship between alcohol and seizures is complex and multifaceted. The prevalence of epilepsy in alcohol-dependent patients of western industrialised countries may be at least triple that in the general population, whereas the prevalence of alcoholism is only slightly higher in patients with epilepsy than in the general population. The seizure threshold is raised by alcohol drinking and declines on cessation of drinking. As a result, during withdrawal from alcohol, usually 6-48 hours after the cessation of drinking, seizures may occur. Alcohol acts on the brain through several mechanisms that influence seizure threshold. These include effects on calcium and chloride flux through the ion-gated glutamate NMDA and GABA receptors. During prolonged intoxication, the CNS adapts to the effects of alcohol, resulting in tolerance; however, these adaptive effects seem to be transient, disappearing after alcohol intake is stopped. Although the relationship of seizures to alcohol use is likely to be dose dependent and causal, the available clinical data do not suggest that alcohol use results in seizure genesis. However, a genetic predisposition to alcohol withdrawal seizures is possible. Other seizures in alcohol-dependent individuals may be due to concurrent metabolic, toxic, infectious, traumatic, neoplastic and cerebrovascular diseases and are frequently partial-onset seizures. Alcohol abuse is a major precipitant of status epilepticus (9-25% of cases), which may even be the first-ever seizure type. Prompt treatment of alcohol withdrawal seizures is recommended to prevent status epilepticus. During the detoxification process, primary and secondary preventative measures can be taken. A meta-analysis of controlled trials for the primary prevention of alcohol withdrawal seizures demonstrated a highly significant risk reduction for seizures with benzodiazepines and antiepileptic drugs and an increased risk with antipsychotics. A meta-analysis of randomised, placebo-controlled trials for the secondary prevention of seizures after alcohol withdrawal showed lorazepam to be effective, whereas phenytoin was ineffective. Because withdrawal seizures do not recur if the patient remains abstinent, long-term administration of antiepileptic drugs is unnecessary in abstinent patients. The first seizure not related to alcohol withdrawal should not result in permanent drug treatment in an alcohol-dependent patient, because of poor compliance and the high likelihood of remission. The treatment of alcohol dependence is more important and should be prioritised before the prevention of further seizures.
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PMID:Seizures in alcohol-dependent patients: epidemiology, pathophysiology and management. 1459 42

Pregnenolone sulfate (PS) is an endogenous neurosteroid synthesized by glial cells, which acts as a potent convulsant when injected intracerebroventricularly and intraperitoneally. PS is found in relatively high concentrations in the hippocampus. But its convulsant action in the hippocampus has not been characterized. A range of PS doses were infused directly into the right hippocampus of 42 rats, which were subsequently monitored for behavioral and electrographic seizures. At the highest dose (4 micromol), PS produced status epilepticus (SE) and severe behavioral convulsions. As the dose of PS was reduced, the fraction of rats having SE diminished (ED50 for SE = 2.7 micromol). At doses lower than 300 nmol, PS infusion produced discrete electrographic seizures (ED50 = 68 nmol) associated with mild behavioral seizures. Both the behavioral seizure score (BSS) and the total number of seizures during the observation period changed in a dose-dependent manner. In separate experiments in cultured hippocampal neurons, PS enhanced NMDA-evoked whole-cell currents (EC50 = 16 microM). The results demonstrate that the hippocampus is highly sensitive to the convulsant effects of PS and that the enhancement of NMDA currents could contribute to the convulsant action of PS.
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PMID:Characterization of the convulsant action of pregnenolone sulfate. 1503 45

Three different classes of NMDA receptor antagonists were compared for their effectiveness in terminating prolonged status epilepticus (SE), induced by continuous hippocampal stimulation. Animals were treated after 150 min of SE by intraperitoneal administration of increasing doses of 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), MK-801 (dizocilpine), ifenprodil, or saline. EEG recordings were used to determine seizure termination. The first experiment (n = 57 animals) determined the most effective anticonvulsant dose of each agent by determining its ability to terminate SE within the next 300 min. Five control rats treated with normal saline after 150 min of SE continued to exhibit continuous seizures for the next 300 min. All drugs were administered after 150 min of SE. CPP terminated seizures with an ED(50) of 6.4 mg/kg; the maximal effective dose was 15 mg/kg. MK-801 has an ED(50) of 1.4 mg/kg; the maximal effective dose was 2 mg/kg. Ifenprodil was maximally effective at 30 mg/kg. However, an ED(50) could not be calculated. In a subsequent experiment, the NMDA antagonists were compared for their ability to terminate prolonged SE within 60 min of their administration at the most effective dose. MK-801 (2.0 mg/kg) terminated SE in 6 of 10 animals within 60 min, CPP (15 mg/kg) terminated it in 1 of 9 animals; ifenprodil (30 mg/kg) did not terminate it in any of 9 animals treated. In the 300 min following administration, CPP (6/9) and MK-801 (6/10) were equally efficacious in terminating SE but ifenprodil (2/7) was less effective (P = 0.065, chi-square test). The results indicate that the non-competitive NMDA receptor antagonist MK-801 was superior to the competitive antagonist CPP and the pH-sensitive site antagonist ifenprodil, in terminating prolonged experimental SE.
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PMID:A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus. 1513 66

Cognitive impairments frequently accompany epileptic disorders. Here, we examine two neuroprotective agents, the noncompetitive NMDA antagonist ketamine and the dopaminergic antagonist acepromazine, for their efficacy in attenuating cognitive impairments in the lithium-pilocarpine (LI-PILO) model of rat limbic epilepsy. Declarative-like cognitive behaviors were assessed in a Morris water maze task that consisted successively of spatial and nonspatial (cued platform) training. Whereas the ketamine-treated (Ket) LI-PILO rats performed equally in all respects to nonseized control rats for the spatial and nonspatial components of the water maze task, the acepromazine-treated (Ace) LI-PILO rats failed to demonstrate learning in either the hidden or cued platform variants of the task and did not demonstrate any place learning in the platform-removed probe trials. We further assessed nondeclarative (associative) cognitive behaviors with a standard contextual fear-conditioning protocol. LI-PILO rats treated with acepromazine failed to learn the Pavlovian relationship; Ket LI-PILO rats performed equivalently to nonseized controls. Cumulatively, these data suggest robust cognitive sparing for LI-PILO rats with pharmacological NMDA receptor antagonism following induction of status epilepticus (SE). This cognitive sparing occurs despite earlier findings that the mean amount of total brain damage with LI-PILO is equivalent for Ket and Ace rats.
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PMID:Normal spatial and contextual learning for ketamine-treated rats in the pilocarpine epilepsy model. 1515 40

Epilepsy or the occurrence of spontaneous recurrent epileptiform discharges (SREDs, seizures) is one of the most common neurological disorders. Shift in the balance of brain between excitatory and inhibitory functions due to different types of structural or functional alterations may cause epileptiform discharges. N-Methyl-D-aspartate (NMDA) receptor dysfunctions have been implicated in modulating seizure activities. Seizures and epilepsy are clearly dependent on elevated intracellular calcium concentration ([Ca2+]i) by NMDA receptor activation and can be prevented by NMDA antagonists. This perturbed [Ca2+]i levels is forerunner of neuronal death. However, therapeutic tools of elevated [Ca2+]i level during status epilepticus (SE) and SREDs have not been discovered yet. Our previous study showed fast inhibition of ginseng total saponins and ginsenoside Rg3 on NMDA receptor-mediated [Ca2+]i in cultured hippocampal neurons. We, therefore, examined the direct modulation of ginseng on hippocampal neuronal culture model of epilepsy using fura-2-based digital Ca2+ imaging and neuronal viability assays. We found that ginseng total saponins and ginsenoside Rg3 inhibited Mg2+ free-induced increase of [Ca2+]i and spontaneous [Ca2+]i oscillations in cultured rat hippocampal neurons. These results suggest that ginseng may play a neuroprotective role in perturbed homeostasis of [Ca2+]i and neuronal cell death via the inhibition of NMDA receptor-induced SE or SREDs.
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PMID:Ginsenosides inhibit NMDA receptor-mediated epileptic discharges in cultured hippocampal neurons. 1520 58

The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including a glutamatergic phase that is inhibited by NMDA antagonists. The present study determined whether 1-aminocyclopropanecarboxylic acid (ACPC) or D-cycloserine (DCS), both partial agonists of the strychnine-insensitive glycine site on the NMDA receptor ionophore complex, exerted anticonvulsant or neuroprotectant activity in Li-pilo SE. ACPC or DCS were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to proceed for 3 h before termination with propofol. The rats were sacrificed 24 h following pilocarpine administration. Neither drug had an effect on the latency to seizure onset or the duration of seizure activity. ACPC administered 5 min after SE onset produced significant neuroprotection in cortical regions, amygdala and CA1 of the hippocampus. In contrast, when administered as exposure treatment ACPC enhanced the neural damage in the thalamus and CA3 of the hippocampus suggesting the neuropathology in those regions is mediated by a different subset of NMDA receptors. DCS had no neuroprotectant activity in Li-pilo SE but exacerbated neuronal damage in the thalamus. Neither drug affected the cholinergic convulsions but both had differential effects on neural damage. This suggests that the SE-induced seizure activity and subsequent neuronal damage involve independent mechanisms.
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PMID:Differential neuroprotective effects of the NMDA receptor-associated glycine site partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and D-cycloserine in lithium-pilocarpine status epilepticus. 1528 14


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