Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined the pharmacological profiles of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-butyrolactone (GBL), a prodrug of gamma-hydroxybutyric acid (GHB). A typical antiabsence drug, ethosuximide (200 mg/kg), attenuated absence seizure behavior, spike and wave and paroxysmal discharges (SWDs and PDs) in each model. P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective gamma-aminobutyric acid (GABA)B antagonist (200 mg/kg), suppressed absence seizure behavior, SWDs and PDs at least as effectively as ethosuximide (200 mg/kg) in lethargic and GHB model mice. P-[3-Aminopropyl]-P-cyclohexylmethylphosphinic acid (CGP 46381) was more effective than CGP 35348 and ethosuximide in these models. Although the antiabsence effect of CGP 46381 was as strong as that of ethosuximide (200 mg/kg) in stargazer mice, CGP 35348 (200-400 mg/kg) was weaker than ethosuximide. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) antagonist (0.5 mg/kg), had no effects on SWDs and PDs in lethargic or GHB model mice. Although MK-801 (0.5 mg/kg) suppressed SWDs significantly in stargazer mice, irregular electroencephalographic patterns were observed. These results suggest that GABAB receptors play a significant role in the pathogenesis of generalized absence seizures in these models, although the mechanism involved in stargazer mice differ from that in the other two.
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PMID:Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice. 929 89

Experiments were performed to examine the roles of gamma-aminobutyric acid(B) (GABA(B)) and gamma-hydroxybutyric acid (GHB) receptors in long-term potentiation (LTP) of the hippocampal CA1 region in vivo and in the genesis of the spike and wave discharges (SWDs) associated with absence seizures. When tetanic stimulation was delivered to the CA3 region, stable LTP was observed in the CA1 region in saline-treated mice. In mice treated with 5 mg/kg baclofen, the population spike amplitude was significantly potentiated by tetanic stimulation and the degree of potentiation was the same as that induced in saline controls. However, this potentiation decayed to the baseline level about 90 min after stimulation. The decay was reversed by pretreatment with 200 mg/kg P-[3-aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective GABA(B) receptor antagonist. In mice treated with 50 mg/kg gamma-butyrolactone (GBL), a prodrug of GHB, stable LTP was observed 90 min after tetanic stimulation and was greater than that in saline controls. GBL-induced potentiation of LTP was antagonized by 50 mg/kg NCS 382, a putative GHB receptor antagonist. Administration of baclofen (20 mg/kg) or GBL (70 mg/kg) induced absence-like seizures associated with 3-6 Hz SWDs, and CGP 35348 suppressed both baclofen- and GBL-induced SWDs. NCS 382 also attenuated SWDs induced by GBL and baclofen. These results suggest that baclofen and GHB have different effects on LTP in the CA1 region of the hippocampus in vivo, although they have a common mode of action on the thalamocortical functions related to the pathogenesis of absence seizures.
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PMID:Roles of gamma-aminobutyric acidB (GABA B) and gamma-hydroxybutyric acid receptors in hippocampal long-term potentiation and pathogenesis of absence seizures. 935 66

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) is a novel neurosteroid which has anticonvulsant properties in a number of seizure models as well as the ability to enhance function of the gamma-aminobutyric acid-A (GABA(A)) receptor complex via a neurosteroid binding site. The object of these experiments was to ascertain the efficacy of ganaxolone against absence seizures. Ganaxolone was assessed in the low-dose pentylenetetrazol (PTZ) and the gamma-hydroxybutyric acid (GHB) model of absence seizures in rats. Ganaxolone pretreatment resulted in a significant prolongation of absence seizure in both the PTZ and GHB models. Further, ganaxolone in doses above 20 mg/kg alone produced bilaterally synchronous spike wave discharges (SWDs) associated with behavioral arrest. These data suggest that augmentation of GABA(A) receptor complex function by neurosteroids has the potential to result in or exacerbate absence seizures.
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PMID:Ganaxolone, a selective, high-affinity steroid modulator of the gamma-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence. 977 70

Interaction of gamma-aminobutyric acid (GABA), pentobarbital and two neuroactive steroids on t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABAA receptors in thalamus was studied during absence seizures. In control brain sections, the steroids alphaxalone and tetrahydrodeoxycorticosterone (at low 0.1-1 microM concentrations) increased [35S]TBPS binding in thalamic relay nuclei. Both GABA and pentobarbital dose-dependently decreased [35S]TBPS binding in these nuclei. A significant decrease in the ability of steroids to increase [35S]TBPS binding in thalamic relay nuclei was observed during absence seizures induced by gamma-hydroxybutyric acid (GHB). This loss of steroid effect on binding was 1) selective to steroids only as GABA and pentobarbital modulation of [35S]TBPS binding in these nuclei did not change significantly and 2) not causally related to the generation of GHB-induced absence seizures as it was not observed at the onset of GHB-seizures but developed 30 min after the seizure-onset. We tested whether absence seizures were critical for the development of this loss of steroid effect on [35S]TBPS binding in thalamic relay nuclei. The ability of the steroids to increase [35S]TBPS binding in relay nuclei was preserved when GHB-seizures were blocked. When the duration of GHB-seizures was prolonged, the loss of steroid effect on [35S]TBPS binding in thalamus persisted throughout the seizure-duration. These findings suggest that absence seizures cause a rapid loss of steroid effect on [35S]TBPS binding to GABAA receptors in thalamic relay nuclei.
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PMID:Absence seizures decrease steroid modulation of t-[35S]butylbicyclophosphorothionate binding in thalamic relay nuclei. 980 8

Certain naturally-occurring steroid metabolites and their synthetic analogs (neuroactive steroids) allosterically enhance GABA(A) receptor function and possess potent anticonvulsant properties. In the present study, the effect of two synthetic neuroactive steroids, alphaxalone (5alpha-pregnane 3alpha-ol-11, 20-dione) and tetrahydrodeoxycorticosterone was studied in a rat model of generalized absence seizures induced by gamma-hydroxybutyric acid. Both steroids dose-dependently exacerbated gamma-hydroxybutyric acid-induced absence seizures upon systemic administration and after focal administration into thalamic ventrobasal nucleus. However, alphaxalone and tetrahydrodeoxycorticosterone failed to potentiate gamma-hydroxybutyric acid-induced absence seizures when injected into thalamic reticular nucleus. In all the doses of steroids tested in thalamic reticular nucleus, the duration of gamma-hydroxybutyric acid-seizures was neither prolonged nor shortened. This nonresponsiveness of thalamic reticular nucleus to neuroactive steroids in modulating absence seizures may have arisen due to the molecular heterogeneity of GABA(A) receptor subunits within the thalamus.
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PMID:Neuroactive steroids exacerbate gamma-hydroxybutyric acid-induced absence seizures in rats. 983 Dec 91

gamma-Hydroxybutyric acid (GHB), a naturally occurring analog of GABA, induces absence-like seizures in rats. We characterized the interaction of 3alpha-hydroxy steroids, alphaxalone and tetrahydrodeoxycorticosterone (which are potent modulators of GABAA receptors) with GHB binding sites in rat brain cortical membranes. The steroids inhibited [3H]GHB binding in a dose-dependent fashion (IC50 approximately 1 microM). Neither bicuculline nor GABA altered the dose-response of steroids in the [3H]GHB assay, suggesting that there was no GABAA component involved in the steroid-inhibition of [3H]GHB binding. Also, non 3alpha-hydroxy steroids were inactive in displacing [3H]GHB. Because GHB-induced absence seizures evolve most readily from layers I-IV of frontoparietal cortex and thalamic relay nuclei, we determined if the interaction of steroids with GHB binding sites in layers I-IV of frontoparietal cortex and thalamic relay nuclei was altered during GHB-induced absence seizures. We found that during GHB-seizures steroid-inhibition of [3H]GHB binding was increased selectively in thalamic relay nuclei but not in the layers I-IV of frontoparietal cortex or any other brain regions tested. This increase in steroid-inhibition of [3H]GHB binding in thalamus was apparent about 30 min after the onset of seizures, but not at the seizure-onset. As the seizures dissipated, the IC50 values for steroids rose to the pre-seizure level. These data suggest that the enhancement in steroid-inhibition of [3H]GHB binding in thalamic relay nuclei observed during GHB-seizures was caused by absence seizures.
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PMID:Steroid-inhibition of [3H]gamma-hydroxybutyric acid (GHB) binding in thalamic relay nuclei increases during absence seizures. 983 87

Modification of GABAA receptor mRNA levels by seizure activity can regulate general neuronal excitability. The possibility of absence seizure-induced alteration in GABAA receptor alpha 1, alpha 4, beta 2, and gamma 2 subunit gene expression in thalamic relay nuclei was studied in a rat model of absence seizures induced by gamma-hydroxybutyric acid (GHB). We observed a marked increase in alpha 1 mRNA and a corresponding decrease in alpha 4 mRNA in thalamic relay nuclei 2-4 h after the onset of GHB-induced absence seizures (when the seizures were terminating). These changes were selective to these alpha isoforms as neither beta 2 nor gamma 2 mRNA changed following seizures and occurred only in thalamic relay nuclei but not in hippocampus, a structure from which absence seizures do not evolve. The alterations in alpha 1 and alpha 4 mRNA persisted until about 12 h, and by 24 h after the seizure-onset the mRNA levels normalized. Blocking GHB-seizures produced no change in the levels of alpha 1 and alpha 4 mRNA in thalamic relay nuclei, suggesting that seizures themselves were responsible for mRNA alterations. In order to determine if absence seizure-induced changes in alpha 1 and alpha 4 mRNA had any physiological significance, GHB was readministered in rats 6 and 24 h after the onset of seizures. The total duration of GHB-seizures was found to be significantly decreased when GHB was readministered at 6 h but not 24 h after the seizure-onset. These results suggest that absence seizures regulate GABAA receptor alpha 1 and alpha 4 gene expression in thalamic relay nuclei as a compensatory mechanism by which absence seizures are terminated.
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PMID:Alterations in GABAA receptor alpha 1 and alpha 4 subunit mRNA levels in thalamic relay nuclei following absence-like seizures in rats. 987 82

Valproate is currently one of the major antiepileptic drugs with efficacy for the treatment of both generalized and partial seizures in adults and children. Furthermore, the drug is increasingly used for therapy of bipolar and schizoaffective disorders, neuropathic pain and for prophylactic treatment of migraine. These various therapeutic effects are reflected in preclinical models, including a variety of animal models of seizures or epilepsy. The incidence of toxicity associated with the clinical use of valproate is low, but two rare toxic effects, idiosyncratic fatal hepatotoxicity and teratogenicity, necessitate precautions in risk patient populations. Studies from animal models on structure-relationships indicate that the mechanisms leading to hepatotoxicity and teratogenicity are distinct and also differ from the mechanisms of anticonvulsant action of valproate. 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 synthesis and release 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 attenuate neuronal excitation induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate exerts direct effects on excitable membranes, although the importance of this action is equivocal. Microdialysis data suggest that valproate alters dopaminergic and serotonergic functions. Valproate is metabolized to several pharmacologically active metabolites, but because of the low plasma and brain concentrations of these compounds it is not likely that they contribute significantly to the anticonvulsant and toxic effects of treatment with the parent drug. By the experimental observations summarized in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels of valproate's mechanisms of action.
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PMID:Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. 1032 96

We explored the involvement of the glutamate receptor subunit B (GluR2) in the mechanism of absence seizures induced by gamma-hydroxybutyric acid (GHB). The expression and distribution of GluR2 protein in rat brain were examined during and after GHB-induced absence seizures. The data indicate that GluR2 protein expression significantly decreases following the onset of absence seizures. The suppression of GluR2 expression was prolonged and it outlasted the duration of the continuous absence seizure activity. The alteration of GluR2 protein levels was accompanied by a re-distribution of GluR2 expression from laminae V to IV in cerebral cortex. We also analyzed the duration and latency of absence seizures induced by GHB 72 h following an initial GHB-induced absence seizure, a time when suppression of GluR2 protein was maximal. The second absence seizure was significantly more prolonged than the first. These data may indicate that the putative down-regulation of GluR2 following GHB-induced absence seizure could have contributed to the potentiation of subsequent seizures in animals. A related hypothesis posed by the data is that down-regulation of GluR2 is involved in the mechanisms of the maintenance of recurrent absence seizure activity once it is initiated and therefore, may contribute to the chronicity of seizures in absence epilepsy.
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PMID:Alteration of GLUR2 expression in the rat brain following absence seizures induced by gamma-hydroxybutyric acid. 1125 72

The present study investigates the activity of four gamma-hydroxybutyric acid amide analogues (BM-68, BM-74, BM-75 and BM-76) in two models of chemically induced seizures, i.e. picrotoxin- and pentetrazole-induced seizures and in the thiopental-induced sleep test. The results of pharmacological in vivo experiments with the gamma-hydroxybutyric acid amide analogues presented below show that the compounds possess variable influence on the central nervous system in mice.
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PMID:Influence of new gamma-hydroxybutyric acid amide analogues on the central nervous system activity in mice. 1286 34


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