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 obtained a neurotoxic fraction (AcTx) from star fruit (Averrhoa carambola) and studied its effects on GABAergic and glutamatergic transmission systems. AcTx had no effect on GABA/glutamate uptake or release, or on glutamate binding. However, it specifically inhibited GABA binding in a concentration-dependent manner (IC(50)=0.89muM). Video-electroencephalogram recordings demonstrated that following cortical administration of AcTx, animals showed behavioral changes, including tonic-clonic seizures, evolving into status epilepticus, accompanied by cortical epileptiform activity. Chemical characterization of AcTx showed that this compound is a nonproteic molecule with a molecular weight less than 500, differing from oxalic acid. This neurotoxic fraction of star fruit may be considered a new tool for neurochemical and neuroethological research.
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PMID:Convulsant activity and neurochemical alterations induced by a fraction obtained from fruit Averrhoa carambola (Oxalidaceae: Geraniales). 1584 46

To understand how nicotinic cholinergic receptors may participate in epileptic seizures, we tested the effects of nicotine and of the competitive nicotinic antagonists dihydro-beta-erythroidine and alpha-bungarotoxin on synaptic paroxysmal depolarization shifts (PDSs) and intrinsic bursts of action potentials recorded in slices from rats presenting a cortical status epilepticus. This model named GABA-withdrawal syndrome (GWS) appears consecutive to the interruption of a prolonged intracortical GABA infusion. Effects of both nicotinic antagonists suggest a distinct involvement of alpha4-beta2 and alpha7 subunits in shaping individual PDSs and patterning repetitive bursts. On one hand, in GWS rats, an increase of PDS latency and prolongation of PDS and bursts were induced by nicotine and reduced by dihydro-beta-erythroidine, but not by alpha-bungarotoxin. The K+ blocker tetraethylammonium also increased duration without changing latency. Thus, dihydro-beta-erythroidine-sensitive receptors exert distinct controls on the presynaptic generation of PDS and on the process which terminates PDSs and bursts. On the other hand, alpha-bungarotoxin depolarized neurons and generated rhythmic discharges of clustered bursts. Clustered bursts were also observed in slices obtained from GWS rats treated with the acetylcholinesterase inhibitor eserine. We suggest that both dihydro-beta-erythroidine and alpha-bungarotoxin-sensitive sites control paroxysmic activities in GWS and could be involved in some human and animal epilepsies presenting mutations of nicotinic cholinergic receptors.
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PMID:Exaggeration of epileptic-like patterns by nicotine receptor activation during the GABA withdrawal syndrome. 1585 85

Status epilepticus is a neurological emergency that results in mortality and neurological morbidity. It has been postulated that the reduction of inhibitory transmission during status epilepticus results from a rapid modification of GABA(A) receptors. However, the mechanism(s) that contributes to this modification has not been elucidated. We report, using an in vitro model of status epilepticus combined with electrophysiological and cellular imaging techniques, that prolonged epileptiform bursting results in a reduction of GABA-mediated synaptic inhibition. Furthermore, we found that constitutive internalization of GABA(A) receptors is rapid and accelerated by the increased neuronal activity associated with seizures. Inhibition of neuronal activity reduced the rate of internalization. These findings suggest that the rate of GABA(A) receptor internalization is regulated by neuronal activity and its acceleration contributes to the reduction of inhibitory transmission observed during prolonged seizures.
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PMID:Status epilepticus increases the intracellular accumulation of GABAA receptors. 1676 Oct 75

Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. Changes in the expression of GABA(A) and GABA(B) receptor mRNAs were observed in both models, and compared with those seen in other models and in human temporal lobe epilepsy. The most prominent changes were a relatively fast (24 h after kindling and electrically-induced SE) and lasting (7 and 30 days after termination of kindling and SE, respectively) reduction of GABA(A) receptor subunit delta mRNA levels (by 43-78%) in dentate granule cells, accompanied by increases in mRNA levels of all three beta-subunits (by 8-79%) and subunit gamma2 (by 11-43%). Levels of the minor subunit alpha4 were increased by up to 60% in dentate granule cells in both animal models, whereas those of subunit alpha5 were decreased 24 h and 30 days after SE, but not after kindling. In cornu ammonis 3 pyramidal cells, downregulation of subunits alpha2, alpha4, alpha5, and beta1-3 was observed in the ventral hippocampus and of alpha2, alpha5, beta3 and gamma2 in its dorsal extension 24 h after SE. Similar but less pronounced changes were seen in sector cornu ammonis 1. Persistent decreases in subunit alpha2, alpha4 and beta2 transcript levels were presumably related to SE-induced cell loss. GABA(B) receptor expression was characterized by increases in GABA(B)R2 mRNA levels at all intervals after kindling and SE. The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.
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PMID:Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. 1595 Nov 23

Venoms of spiders and wasps are well recognized to present high affinity to the central nervous tissue of many mammalian species. Here we describe the effects of direct exposure of rat (Rattus norvegicus) brains to the crude and denatured venom of the Brazilian social wasp Polybia ignobilis. Lower doses of crude venom injected via intracerebroventricular (i.c.v.) inhibited the exploratory activity of animals, while higher doses provoked severe generalized tonic-clonic seizures, with hind limb extension. The status epilepticus lasted for few minutes leading the animals to respiratory depression and death. In contrast, the denatured venom was anticonvulsant against acute seizures induced by the i.c.v. injection of bicuculline, picrotoxin and kainic acid, but it was ineffective against seizures caused by systemic pentylenetetrazole. Moreover, the [3H]-glutamate binding in membranes from rat brain cortex was inhibited by the denatured venom in lower concentrations than the [3H]-GABA binding. The denatured venom contains free GABA and glutamate (34 and 802 pg/microg of venom, respectively), but they are not the major binding inhibitors. These interactions of venom components with GABA and glutamate receptors could be responsible for the anticonvulsant effects introducing the venom from P. ignobilis as a potential pharmacological source of anticonvulsant drugs.
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PMID:Anticonvulsant effects of the wasp Polybia ignobilis venom on chemically induced seizures and action on GABA and glutamate receptors. 1595 69

GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABA(A) receptor, including increased levels of alpha4 subunit in dentate granule cells and associated functional alterations such as increased zinc blockade of GABA currents, are hypothesized to be critical components of epileptogenesis. Here, we report that the minimal promoter of the human alpha4 subunit gene (GABRA4p), when used to drive reporter gene expression from adeno-associated viral vectors, controls condition-specific up-regulation in response to status epilepticus, defining a transcriptional mechanism for seizure-induced changes in levels of alpha4 subunit containing GABA(A) receptors. Transfection studies in primary hippocampal neurons show that inducible early growth response factor 3 (Egr3) up-regulates GABRA4p activity as well as the levels of endogenous alpha4 subunits. Given that Egr3 knockout mice display approximately 50% less GABRA4 mRNAs in the hippocampus and that increases in alpha4 and Egr3 mRNAs in response to pilocarpine-induced status epilepticus are accompanied by increased binding of Egr3 to GABRA4 in dentate granule cells, our findings support a role for Egr3 as a major regulator of GABRA4 in developing neurons and in epilepsy.
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PMID:Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. 1609 74

During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta2/beta3 and gamma2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA(A) tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA(A) receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA(A) current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA(A) postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.
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PMID:Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. 1676 Oct 75

Increased brain histamine is reported to protect against convulsions. We used systemic kainic acid (KA) administration to study possible changes of the histaminergic system in rat brain in status epilepticus (SE). Robust increases in brain histamine concentrations and numbers of histamine-immunoreactive nerve fibers were detected in the piriform cortex (Pir) and amygdala after KA injection, suggesting a reactive increase, which is opposite to other published aminergic transmitter responses. These changes, lasting several weeks, might be coupled to a mechanism unrelated to the anticonvulsive function of histamine. Transient increases in mRNA expression of H(3) receptor isoforms with a full-length third intracellular loop, coupled to mitogen-activated protein kinase pathway, were detected first in the hippocampal CA3c area, followed by the Pir and amygdala and then the hippocampal CA1 area. These results suggest that histamine and H3 receptors, which also control the release of GABA and glutamate, might be involved in convulsive SE.
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PMID:Transient changes in the limbic histaminergic system after systemic kainic acid-induced seizures. 1613 76

Murine models of inborn errors of metabolism represent an established approach for investigating pathophysiological mechanisms associated with the corresponding human disorder. Our laboratory studies human inherited defects of GABA synthesis and degradation. One of these, succinate semialdehyde dehydrogenase (SSADH) deficiency (or gamma-hydroxybutyric aciduria; OMIM 271980; E.C. 1.2.1.24), has recently been modeled via gene targeting in the mouse. SSADH-/- mice succumb to early lethality in status epilepticus at postnatal (PN) days 20 - 26. Numerous metabolic, neurochemical and neurophysiological abnormalities have been documented using in vitro and in vivo approaches, substantially altering our thoughts about the complexity of the corresponding human condition. Moreover, novel preclinical treatment paradigms have been developed through drug trials in gene-ablated animals. The greatest utility of this animal, however, may reside in its transition from early absence seizures to generalized convulsions and eventual status epilepticus. Accurate neurochemical assessment during this transition may provide clues to the same transition process in patients, for which the underlying mechanisms remain undefined.
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PMID:Murine succinate semialdehyde dehydrogenase (SSADH) deficiency, a heritable disorder of GABA metabolism with epileptic phenotype. 1620 83

The epilepsy that occurs in SSADH deficiency has a seizure phenotype similar to that occurring in the SSADH(-/-) mouse. We examined the expression and function of the GABA(A) receptor (GABA(A)R) in SSADH-deficient mice. A selective decrease in binding of [(35)S]tert-butylbicyclophosphorothionate was observed in SSADH(-/-) mice at postnatal day 7 that was progressive until the third postnatal week of life when, at the nadir of the decreased [(35)S]tert-butylbicyclophosphorothionate binding, generalized convulsive seizures emerged that rapidly evolved into status epilepticus. We also observed a substantial downregulation of the beta(2) subunit of GABA(A)R, a reduction in GABA(A)-mediated inhibitory postsynaptic potentials, and augmented postsynaptic population spikes recorded from hippocampal slices. The SSADH(-/-) mouse model represents a powerful investigative tool for understanding the pathophysiology of the seizures associated with human SSADH deficiency. These data raise the possibility that progressive dysfunction of the GABA(A)R may be involved in the development of seizures in SSDAH-deficient mice. Elucidation of the precise fundamental mechanisms of the perturbation of the GABA(A)R-mediated function in SSADH(-/-) mice could lead to the development of novel treatment modalities designed to reduce the neurological morbidity in children with SSADH deficiency.
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PMID:Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms. 1624 Mar 71


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