Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some 3,3-disubstituted 2-pyrrolidinones and 2-piperidinones (five- and six-membered ring lactams, respectively) possess potent in vivo anticonvulsant activity. In vitro these lactams potentiate GABA(A) receptor-mediated chloride currents, which is thought to be the mechanism by which they exert their therapeutic effects. However, the apparent affinity for these GABA(A) interactions is low: EC50s range from hundreds of micromolar to low millimolar values. In order to more completely characterize the activities of these compounds, it was necessary to know the concentrations required to curtail epileptiform activity in an intact neural network, and the mechanism by which this occurs. To address these questions, we used two methods of inducing ictal activity in hippocampal-entorhinal cortical slices: 4-aminopyridine (4-AP) and low Mg2+. We found that 3,3-diethyl-2-pyrrolidinone (diethyl-lactam) prevents seizure-like discharges with IC50s of 1.1 and 2.1 mM in the two models, respectively. These values are nearly identical to the EC50 value obtained in whole-cell studies of diethyl-lactam's GABA(A) receptor modulation. The addition of the GABA(A) antagonist picrotoxin to the low Mg2+ ACSF produced seizures which persisted during diethyl-lactam application. Neither 3-benzyl-3-ethyl-2-piperidinone (3-BEP) nor alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL), two compounds which are similar to diethyl-lactam, but demonstrate picrotoxin-insensitive inhibition of voltage-dependent currents, diminished low Mg2+/picrotoxin seizure activity. Our results support the hypothesis that diethyllactam and related compounds exert their anticonvulsant activity primarily, if not exclusively, by modulating the GABA(A) receptor.
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PMID:Effects of anticonvulsant lactams on in vitro seizures in the hippocampal slice preparation. 1051 Sep 78

The GABAergic system has long been implicated in epilepsy with defects in GABA neurotransmission being linked to epilepsy in both experimental animal models and human syndromes (Olsen and Avoli, 1997). However, to date no human epileptic syndrome has been directly attributed to an altered GABAergic system. The observed defects in GABA neurotransmission in human epileptic syndromes may be the indirect result of a brain besieged by seizures. The use of animal models of epilepsy has sought to address these matters. The advent of gene targeting methodologies in mice now allows for a more direct assessment of GABA's involvement in epileptogenesis. To date several genes associated with the GABAergic system have been disrupted. These include the genes for glutamic acid decarboxylase, both the 65- and 67-kDa isoforms (GAD65 and GAD67), the tissue non-specific alkaline phosphatase gene (TNAP) and genes for the GABA(A) receptor subunits alpha6, beta3, gamma2, and delta (gabra6, gabrb3, gabrg2, and gabrd respectively). Gene disruptions of either GAD67 or gabrg2 result in neonatal lethality, while others, GAD65, TNAP, and gabrb3 exhibit increased mortality and spontaneous seizures. GABA receptor expression has been found to be both regionally and developmentally regulated. Thus in addition to their obvious role in controlling excitability in adult brain, a deficit in GABAergic function during development could be expected to elicit pleiotropic neurodevelopmental abnormalities perhaps including epilepsy. The GABA(A) receptor beta3 subunit gene, gabrb3/GABRB3 (mouse/human), is of particular interest because of its expression early in development and its possible role in the neurodevelopmental disorder Angelman syndrome. Individuals with this syndrome exhibit severe mental retardation and epilepsy. Mice with the gabrb3 gene disrupted likewise exhibit electroencephalograph (EEG) abnormalities, seizures, and behavioral characteristics typically associated with Angelman syndrome. These gabrb3 gene knockout mice provide direct evidence that a reduction of a specific subunit of the GABA(A) receptor system can result in epilepsy and support a GABAergic role in the pathophysiology of Angelman syndrome.
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PMID:GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man. 1051 60

Since 1993, several new antiepileptic drugs (AEDs) have been introduced for management of partial seizures. Like the established AEDs, the new drugs are believed to exert their anticonvulsant action through enhancement of inhibitory-mediated neurotransmission, or reduction of excitatory-mediated neurotransmission, or by a combination of both. Among the new drugs, vigabatrin (VGB) and tiagabine (TGB) are unique in that they were derived from mechanistic-based drug discovery programs designed to identify effective AEDs that inhibit the metabolism and reuptake of the inhibitory neurotransmitter GABA, respectively. For many of the newer AEDs, several molecular mechanisms of action have been identified. For example, felbamate (FBM), lamotrigine (LTG), zonisamide (ZNS), topiramate (TPM), oxcarbazepine (OCBZ), and possibly gabapentin (GBP) share a similar mechanism with that defined for phenytoin (PHT) and carbamazepine (CBZ), i.e., a voltage- and use-dependent block of voltage-sensitive sodium (Na+) channels. In addition to their effects on Na+ currents, TPM, ZNS, and FBM also appear to act as allosteric modulators of the GABA(A) receptor, whereas GBP appears to increase brain GABA levels. GBP, ZNS, FBM, LTG, and OCBZ attenuate voltage-sensitive calcium (Ca2+) channels, albeit through different mechanisms and with different classes of Ca2+ channels. FBM and TPM differ from both the established and newer AEDs in their ability to modulate NMDA- and AMPA/kainate-mediated excitatory neurotransmission, respectively. The multiple mechanisms of action associated with FBM, TPM, ZNS, GBP, and perhaps LTG, and the unique modulation of GABA levels by VGB and TGB, are likely to account for the anticonvulsant efficacy of these newer AEDs in patients with epilepsy. For each of the new drugs, their proposed mechanisms of action are discussed in relationship to their preclinical and clinical anticonvulsant profiles.
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PMID:Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. 1053 Jun 88

The present study examined synaptic potentials of neurons in inferior colliculus (IC) cortex slice and the roles of GABA and glutamate receptors in generating these potentials. Multipolar (82%) and elongated (18%) cells were observed with intracellular biocytin staining. Electrical stimulation of the IC commissure (CoIC) elicited only inhibitory postsynaptic potentials (IPSPs) (10% of cells), only excitatory postsynaptic potentials (EPSPs) (51%), or both (38%). IPSPs were elicited at lower thresholds and shorter latencies than EPSPs (mean: 1.6+/-1.2 ms) and IPSPs were observed in all neurons following membrane depolarization. Short-latency EPSPs were blocked by non-NMDA receptor antagonists, and longer-latency EPSPs were blocked by NMDA antagonists. CoIC stimulation evoked short-latency IPSPs (mean: 0.55+/-0.33 ms) in 48% of neurons, and the IPSPs persisted despite glutamate receptor blockade, which implies monosynaptic inhibitory input. A GABA(A) antagonist blocked IPSPs and paired pulse inhibition of EPSPs, suggesting GABA(A) receptor mediation. A GABA(B) antagonist reduced paired pulse inhibition of IPSPs, suggesting GABA(B) receptor modulation. Thus, GABA-mediated inhibition plays a critical role in shaping synaptic responses of IC cortex neurons. Normal GABAergic function in IC has been shown to be important in acoustic coding, and reduced efficacy of GABA function in IC neurons is critical in IC pathophysiology in presbycusis, tinnitus and audiogenic seizures.
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PMID:Synaptic response patterns of neurons in the cortex of rat inferior colliculus. 1054 30

Despite the susceptibility of immature neurons to seizures, there are few models of epilepsy in the developing brain. By taking advantage of activity-dependent developmental changes in young neurons, we have developed a novel model of chronic epilepsy in cultured hippocampal slices. Incubating slices in tetrodotoxin (TTX) for at least 1 week produced significant changes in the electrical activity and appearance of CA1 pyramidal neurons. Extracellular recordings revealed multiple population spikes, and, in whole-cell recordings, evoked synaptic potentials lasting hundreds of milliseconds with many superimposed action potentials were present. Spontaneous firing with burst-like discharges was also evident. These changes were secondary to increased AMPA-receptor-mediated responses and decreased GABA(A) receptor events. Altered membrane properties involved increased expression of T-type Ca(2+) channels which are normally down-regulated in these neurons. TTX-treated neurons also showed abnormal dendritic branching. This model of chronic epilepsy in developing hippocampal neurons demonstrated many changes at the membrane, cellular and synaptic level that may provide new insights into the nature of epileptogenesis in the young brain.
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PMID:Chronic epilepsy in developing hippocampal neurons: electrophysiologic and morphologic features. 1057 56

Interleukin-1beta (IL-1beta), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action on the gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1beta at concentrations encountered in pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the peak magnitude of current elicited by 30 microM GABA. Current inhibition was IL-1beta concentration- and time-dependent and was prevented by a specific IL-1beta type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1beta depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 microM), but not by a protein kinase C selective inhibitor calphostin C (5 microM). We conclude that IL-1beta inhibits GABA(A) receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABA(A) inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.
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PMID:Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. 1064 Feb 85

Repeated seizures induce mossy fiber axon sprouting, which reorganizes synaptic connectivity in the dentate gyrus. To examine the possibility that sprouted mossy fiber axons may form recurrent excitatory circuits, connectivity between granule cells in the dentate gyrus was examined in transverse hippocampal slices from normal rats and epileptic rats that experienced seizures induced by kindling and kainic acid. The experiments were designed to functionally assess seizure-induced development of recurrent circuitry by exploiting information available about the time course of seizure-induced synaptic reorganization in the kindling model and detailed anatomic characterization of sprouted fibers in the kainic acid model. When recurrent inhibitory circuits were blocked by the GABA(A) receptor antagonist bicuculline, focal application of glutamate microdrops at locations in the granule cell layer remote from the recorded granule cell evoked trains of excitatory postsynaptic potentials (EPSPs) and population burst discharges in epileptic rats, which were never observed in slices from normal rats. The EPSPs and burst discharges were blocked by bath application of 1 microM tetrodotoxin and were therefore dependent on network-driven synaptic events. Excitatory connections were detected between blades of the dentate gyrus in hippocampal slices from rats that experienced kainic acid-induced status epilepticus. Trains of EPSPs and burst discharges were also evoked in granule cells from kindled rats obtained after > or = 1 wk of kindled seizures, but were not evoked in slices examined 24 h after a single afterdischarge, before the development of sprouting. Excitatory connectivity between blades of the dentate gyrus was also assessed in slices deafferented by transection of the perforant path, and bathed in artificial cerebrospinal fluid (ACSF) containing bicuculline to block GABA(A) receptor-dependent recurrent inhibitory circuits and 10 mM [Ca(2+)](o) to suppress polysynaptic activity. Low-intensity electrical stimulation of the infrapyramidal blade under these conditions failed to evoke a response in suprapyramidal granule cells from normal rats (n = 15), but in slices from epileptic rats evoked an EPSP at a short latency (2.59 +/- 0.36 ms) in 5 of 18 suprapyramidal granule cells. The results are consistent with formation of monosynaptic excitatory connections between blades of the dentate gyrus. Recurrent excitatory circuits developed in the dentate gyrus of epileptic rats in a time course that corresponded to the development of mossy fiber sprouting and demonstrated patterns of functional connectivity corresponding to anatomic features of the sprouted mossy fiber pathway.
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PMID:Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. 1066 85

Mice with an inactivated GABA(A) receptor beta(3) subunit gene have features of Angelman syndrome, including absence-like seizures. This suggests the occurrence of abnormal hypersynchrony in the thalamocortical system. Within the thalamus, the efficacy of inhibitory synapses between thalamic reticular (RE) neurons is selectively compromised, and thalamic oscillations in vitro are prolonged and lack spatial phase gradients (). Here we used computational models to examine how intra-RE inhibition regulates intrathalamic oscillations. A major effect is an abbreviation of network responses, which is caused by long-lasting intra-RE inhibition that shunts recurrent excitatory input. In addition, differential activation of RE cells desynchronizes network activity. Near the slice center, where many cells are initially activated, there is a resultant high level of intra-RE inhibition. This leads to RE cell burst truncation in the central region and a gradient in the timing of thalamocortical cell activity similar to that observed in vitro. Although RE cell burst durations were shortened by this mechanism, there was very little effect on the times at which RE cells began to burst. The above results depended on widespread stimuli that activated RE cells in regions larger than the diameter of intra-RE connections. By contrast, more focal stimuli could elicit oscillations that lasted several cycles and remained confined to a small region. These results suggest that intra-RE inhibition restricts intrathalamic activity to particular spatiotemporal patterns to allow focal recurrent activity that may be relevant for normal thalamocortical function while preventing widespread synchronization as occurs in seizures.
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PMID:Reciprocal inhibitory connections regulate the spatiotemporal properties of intrathalamic oscillations. 1068 75

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.
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PMID:Selective susceptibility to inhibitors of GABA synthesis and antagonists of GABA(A) receptor in rats with genetic absence epilepsy. 1068 90

The sharp interruption of the intracortical instillation of exogenous gamma-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 microM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3alpha-OH-5alpha-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABA(A) receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABA(A) receptor agonists.
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PMID:Neocortical hyperexcitability after GABA withdrawal in vitro. 1069 Jul 49


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