UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible role of thalamic NMDA receptors in the generation of experimental absence-like seizures was studied in rats. Bilaterally synchronous spike wave discharges were induced by gamma-hydroxybutyric acid (GHB) and were recorded simultaneously from different thalamic nuclei and the layers I-IV of frontoparietal cortex. Bilateral infusions of NMDA into thalamic mediodorsal nucleus, the intralaminar central lateral/paracentral nucleus, ventroposterolateral, or reticular nucleus of the thalamus in conscious rats, prior to GHB administration suppressed GHB-induced SWD in a dose dependent manner. However, no such suppression of GHB-induced SWD was observed when NMDA infusions were made into the above thalamic sites after the onset or development of GHB-induced SWD. Pretreatment with high doses of competitive (CGP 43487) or non-competitive NMDA receptor antagonists (MK-801 and ketamine) also dose dependently suppressed GHB-induced SWD. Both MK-801 and CGP 43487 dose dependently antagonized NMDA-mediated inhibition of GHB-induced SWD activity but at lower doses did not produce significant inhibition of GHB-induced SWD. The anti-SWD effects of NMDA, MK-801 and ketamine but not CGP 43487 were more pronounced in the mediodorsal and intralaminar thalamic nuclei than in the ventroposterolateral or reticular nucleus of thalamus. Because low doses of NMDA antagonists failed to disrupt the generation of seizures in the GHB model, these findings do not support a role for thalamic NMDA receptors in the pathogenesis of absence-like seizures induced by gamma-hydroxybutyric acid.
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PMID:Thalamic NMDA receptors in the gamma-hydroxybutyrate model of absence seizures: a cerebral microinjection study in rats. 762 63

The ventrobasal nucleus of thalamus (VB) is considered to be intimately involved in the genesis of experimental absence-like seizures. Bilateral microinfusion of gamma-hydroxybutyric acid (GHB) into VB or systemic administration of gamma-butyrolactone, the pro-drug of GHB, induces generalized absence-like seizures in rats. In the present study, the basal and K(+)-evoked extracellular output of endogenous gamma-aminobutyric acid (GABA) and glutamate (GLU) in behaving rat VB nucleus was characterized 1) during unilateral GHB perfusion into VB and 2) during the course of generalized absence-like seizures induced by GHB. Although the basal extracellular release of GABA was inhibited by GHB (250-1500 microM) in a concentration-dependent manner, basal GLU levels remained unaltered. However, K(+)-evoked release of both GABA and GLU was significantly attenuated by GHB. During GHB-induced absence-like seizures, a similar decrease in basal GABA or K(+)-evoked GABA and GLU levels was observed. These effects of GHB were partially reversed by the specific GHB receptor antagonist NCS 382. (-)-Baclofen (10-50 microM) also produced a concentration-dependent decrease in basal and K(+)-evoked levels of GABA and GLU in this thalamic nucleus. The effects of either (-)-baclofen or GHB on the release of GABA and GLU were selectively antagonized by the GABAB receptor antagonists phaclofen (0.75-2 mM) and CGP 35348 (50-200 microM), respectively. These results suggest that by selectively modulating the basal and K(+)-evoked release of GABA and GLU, GHB induces, in the thalamic ventrobasal relay nucleus, an optimal "excitatory" environment conducive to the generation of absence seizures. Moreover, the data raise the possibility that a presynaptic GHB/GABAB receptor complex occurs in VB.
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PMID:Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB. 779 Nov 29

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. There is growing evidence that both gamma-aminobutyric acid (GABA)B- and GHB-mediated mechanisms are involved in the pathogenesis of this phenomenon. Because of the fact that absence seizures are a disorder of children the ontogeny of [3H]GHB and [3H]GABAB binding and the developmental appearance of absence seizures in the GHB model of absence was ascertained and compared in developing rats. [3H]GABAB binding was present within the first 3 days of postnatal life and rose to levels which exceeded those found in adults, peaking between the 3rd and 5th postnatal week. [3H]GHB binding on the other hand did not appear until postnatal day 17 when it was detectable in the CA1 region of the hippocampus. There was a steady increase in [3H]GHB binding until adult levels were reached by postnatal day 40. Comparison of [3H]GABAB and [3H]GHB binding revealed that both sites were common to layer I-III of cortex, but otherwise differed in their regional distribution. There was an absolute concordance of the ontogeny of GHB-induced absence seizures with the developmental appearance of [3H]GHB binding in the superficial laminae of cortex; both appeared at postnatal day 18. These data support the hypotheses that the [3H]GHB and [3H]GABAB binding sites are separate from one another and suggest that maturational events in thalamus and cortex in the 3rd postnatal week are involved in the expression of GHB-induced absence seizures.
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PMID:The ontogeny of [3H]gamma-hydroxybutyrate and [3H]GABAB binding sites: relation to the development of experimental absence seizures. 782 Jun 56

The effect of bilateral electrolytic lesions of various thalamic sites on the generation of bilaterally synchronous spike and wave discharges (SWD) was studied in two experimental rat models of absence-like seizures. SWD induced by both pentylenetetrazole (20 mg/kg, i.p.) and gamma-hydroxybutyric acid (gamma-butyrolactone, 100 mg/kg, i.p.) were recorded simultaneously from the thalamus and cortex. In both models generation of SWD from the mediodorsal, intralaminar (central lateral and paracentral), ventroposterolateral (VPL) and the reticular thalamic (RT) nucleus was synchronous with that of frontoparietal cortex. Bilateral lesions in mediodorsal and intralaminar thalamic nuclei abolished SWD from both cortex and thalamus in both models. Similar lesions in VPL did not abolish, but attenuated the duration of pentylenetetrazole- and gamma-hydroxybutyric acid-induced SWD, more significantly from the thalamus than from the cortex. RT lesions were associated with more pronounced suppression of pentylenetetrazole-, but not gamma-hydroxybutyric acid-induced SWD in the thalamus. These findings suggest a potential role for mediodorsal and intralaminar thalamic nuclei in the generation of experimental absence-like seizures in rats.
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PMID:Thalamic mediodorsal and intralaminar nuclear lesions disrupt the generation of experimentally induced generalized absence-like seizures in rats. 801 43

Valproate is currently one of the major antiepileptic drugs in clinical use. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA turnover and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to block cell firing induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate presumably exerts a direct action on ion channels, thereby limiting sustained repetitive neuronal firing. Recent microdialysis data suggest that valproate also alters dopaminergic and serotonergic functions. These diverse effects of valproate might explain why the drug not only exerts anticonvulsant activity but also other pharmacodynamic and pharmacotherapeutic actions, such as antipsychotic and antidystonic efficacy.
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PMID:Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. 809 95

gamma-Hydroxybutyric acid is a naturally occurring compound which induces bilaterally synchronous spike and wave discharges in rats. The gamma-hydroxybutyric acid model of absence seizures simulates clinical absence seizures behaviorally as well as electrographically. The present study was undertaken in order to establish the role of the high-affinity gamma-hydroxybutyric acid binding sites in the generation of gamma-hydroxybutyric acid-induced spike and wave discharges. Spike and wave discharges induced by gamma-hydroxybutyric acid were recorded with the aid of bipolar depth electrodes implanted in discrete regions of thalamus, cortex and hippocampus. In the present study we found that ventroposterolateral, ventroposteromedial, medial and the reticular nuclei of the thalamus discharged synchronously with the cortical generation of spike and wave discharges. In the cortex, the superficial layers (I-IV) of frontoparietal cortex generated spike and wave discharges, whereas no spike and wave discharges were recorded from deeper layers (V-VI) of frontoparietal cortex. At the onset of spike and wave discharges induced by gamma-hydroxybutyric acid, a rapid but reversible upregulation of gamma-hydroxybutyric acid binding sites was observed. This increased [3H]gamma-hydroxybutyric acid binding was characterized by an increase in the number of gamma-hydroxybutyric acid sites with no significant change in their affinity for gamma-hydroxybutyric acid. Moreover, the change in [3H]gamma-hydroxybutyric acid binding was observed only in those thalamic structures and cortical layers which were found to be involved in the generation of spike and wave discharges induced by gamma-hydroxybutyric acid. The CA3 field or dorsal hippocampus possesses the highest density of [3H]gamma-hydroxybutyric acid binding sites of all brain regions. However, no significant change in [3H]gamma-hydroxybutyric acid binding was observed in this region nor was the CA3 field involved in the generation of spike and wave discharges during gamma-hydroxybutyric acid-induced absence-like seizures. These findings confirm that gamma-hydroxybutyric acid-induced absence-like seizures originate from thalamocortical pathways and that the onset of gamma-hydroxybutyric acid-induced spike and wave discharges is directly related to the regulation of gamma-hydroxybutyric acid binding sites in those regions which constitute the involved thalamocortical loop.
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PMID:gamma-Hydroxybutyric acid induced spike and wave discharges in rats: relation to high-affinity [3H]gamma-hydroxybutyric acid binding sites in the thalamus and cortex. 823 11

gamma-Hydroxybutyric acid (GHB) produces absence-like seizures when given to animals. One of the distinguishing characteristics of experimental generalized absence seizures is that they are exacerbated by GABAA agonists. Therefore, the hypothesis that GHB-induced absence seizures result from an interaction between GHB and the GABAA receptor complex was tested. The effect of GHB on the function of various components of the GABAA receptor complex in the cortex of the rat, was determined in a series of in vitro experiments. Similar studies were carried out at various times following systemic administration of the prodrug of GHB, gamma-butyrolactone (GBL) and changes in the GABAA receptor were correlated with electrographic and behavioral changes. gamma-Hydroxybutyric acid had no effect on the binding of [3H]muscimol, [3H]flunitrazepam and [35S]t-butylbicyclophosphorothionate (TBPS) or on the uptake of 36Cl- into synaptoneurosomes in the in vitro studies. Nor were changes observed after the administration of GBL before the onset of GHB-induced absence seizures. However, at the onset of GHB-induced spike wave discharge, there was a significant (P < 0.04) decrease in the binding of [35S]TBPS, associated with a significant decrease in muscimol-stimulated uptake of 36Cl- with no other biochemical change. One minute after onset of GHB-induced absence seizure, a significant (P < 0.05) increase in the binding of [3H]muscimol was noted. Ten minutes later the decrease in muscimol-stimulated uptake of 36Cl- had normalized, while the changes in binding of [3H]muscimol and [35S]TBPS persisted. Because GABAA function remained unchanged in the in vitro studies, as well as prior to the onset of GHB-induced absence seizures in the in vivo experiments, these studies do not support the hypothesis that GHB interacts directly with the GABAA receptor complex to produce absence-like seizures.
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PMID:GABAA receptor function in the gamma-hydroxybutyrate model of generalized absence seizures. 838 52

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. This effect of GHB may be blocked by either GHB or GABAB receptor antagonists. We sought to test the hypothesis that pre-synaptic GHB- and GABAB-mediated mechanisms in thalamus and cortex are operative in the GHB model of generalized absence seizures. Presynaptic Ca(2+)-dependent K+ efflux was determined using Ca(2+)-stimulated Rb86 efflux in synaptosomes prepared from thalamus and cortex in the presence of GHB, a specific GHB receptor antagonist, the specific GABAB agonist (-)baclofen, or the specific GABAB antagonists, phaclofen and CGP 35348. The effect of these compounds was determined also on basal and K(+)-stimulated 45Ca2+ uptake and basal and K(+)-stimulated synaptosomal cytosolic Ca2+([Ca2]i) in synaptosomes prepared from thalamus and cortex and on [125I] omega-conotoxin binding in thalamus and cortex using autoradiographic binding techniques. There was no demonstrable change in Ca(2+)-stimulated Rb86 efflux in any experimental condition studied; however GHB and (-)baclofen both suppressed K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes and were associated with a decrease in [125I] omega-conotoxin binding which achieved statistical significance only in frontal cortex, a brain region selectively involved in the genesis of GHB-induced absence seizures. The effects of GHB and (-)baclofen on K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes were additive. The effects of GHB in this regard were attenuated by the GHB antagonist and phaclofen while that of (-)baclofen was attenuated by CGP 35348. These data do not support the hypothesis that the GHB and GABAB receptor are one and the same. Rather, they raise the possibility that a presynaptic GHB/GABAB receptor complex might be involved in the pathogenesis of GHB-induced generalized absence seizures.
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PMID:Presynaptic GABAB-and gamma-hydroxybutyric acid-mediated mechanisms in generalized absence seizures. 878 11

Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures possibly by GABAB-receptor-mediated mechanisms. The object of these experiments was to examine the effectiveness of a range of specific GABAB-receptor agonists and antagonists of varying specificity, as well as the specific GHB-receptor antagonist NCS 382, in two experimental animal models of generalized absence seizures: one in which the seizures are induced by GHB and the other in which the seizures are induced by administration of low-dose (20-mg/kg) pentylenetetrazole. All specific GABAB-receptor antagonists as well as the specific GHB-receptor antagonist produced blockade of experimental absence seizures in both models; pretreatment with GABAB-receptor agonists resulted in generalized absence status epilepticus lasting for hours. These data confirm the concept that specific GABAB-receptor antagonist activity confers antiabsence seizure activity, suggest that the same holds for specific GHB-receptor antagonists, and raise the possibility that both GHB- and GABAB-antagonist drugs have the potential to be useful therapeutic agents in generalized absence seizures.
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PMID:Antiabsence seizure activity of specific GABAB and gamma-Hydroxybutyric acid receptor antagonists. 884 63

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals. GHB has been hypothesized to induce this effect via the postsynaptic gamma-aminobutyric acidB (GABAB) receptor. We sought to test this hypothesis by examining the affinity of GABAB agonists and antagonists for the [3H]GHB binding site, the affinity of GHB and a GHB antagonist for the [3H]GABAB binding site, and the effect of guanine nucleotides and pertussis toxin on both, using autoradiographic binding assays. GHB and its antagonist, NCS 382, did not compete for [3H]GABAB binding, nor did (-)-baclofen or the [3H]GABAB antagonists, CGP 35348 or SCH 50911, compete for [3H]GHB binding; however, the GABAB agonist 3-amino-propylphosphinic acid (3-APPA), and the GABAB antagonists phaclofen and 2-hydroxysaclofen (2-OH saclofen) did show a weak affinity for [3H]GHB binding in frontal cortex. GTP and the nonhydrolyzable GTP analogues, GTP gamma S and Gpp(NH)p, depressed [3H]GABAB binding throughout the brain, but increased [3H]GHB binding in frontal cortex and thalamus, those regions involved in GHB-induced absence seizures. Pertussis toxin significantly depressed [3H]GABAB binding throughout the brain, but attenuated [3H]GHB binding only in frontal cortex, and to a lesser degree than [3H]GABAB binding. The guanine nucleotide-induced changes in [3H]GHB and [3H]GABAB binding were due to a change in KD for both. Moreover, GTP gamma S reversed the ability of 3-APPA, phaclofen, and 2-OH saclofen to compete for [3H]GHB binding. These data do not support the hypothesis that GHB acts through the postsynaptic GABAB receptor to produce absence seizures. Rather, they raise the possibility either that the [3H]GHB binding site may be an isoform of the presynaptic GABAB receptor or that an independent GHB site is operative in the GHB model of absence seizures.
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PMID:Relation of the [3H] gamma-hydroxybutyric acid (GHB) binding site to the gamma-aminobutyric acidB (GABAB) receptor in rat brain. 893 31

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