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

Central type benzodiazepine receptors were studied in vivo by positron emission tomography in brain areas of 2 different groups of the baboon Papio papio: non-photosensitive (group 1) and those with an allylglycine-induced decrease in GABA-mediated inhibition (group 2). Further, a naturally photosensitive Papio papio (+3 level of photosensitive response) was compared to both groups. Regional brain binding of the specific benzodiazepine receptor ligand, [11C]Ro 15-1788, was not significantly different between groups 1 and 2. In addition, the data from the naturally photosensitive Papio papio did not seem to differ markedly from groups 1 and 2 either. Pharmacological effects of increasing doses of beta-CCM (0.05-3 mg/kg i.v.) and regional benzodiazepine receptor occupancy by the drug were simultaneously studied using electroencephalographic activity recording and positron emission tomography. A positive correlation was observed between the degree of photosensitivity of the baboon and sensitivity to the action of beta-CCM, with increasing convulsant efficacy of beta-CCM in going from group 1 to the naturally photosensitive baboon, then to group 2. Dose-related displacement curves of [11C]Ro 15-1788 binding by beta-CCM revealed that reduction in brain GABA concentration did not modify the inhibitory potency of beta-CCM on [11C]Ro 15-1788 binding in cerebral cortex. This suggests a lack of detectable in vivo allosteric effects of GABA on beta-CCM binding during beta-CCM-induced seizures. Thus, a given dose of beta-CCM displayed increasing pharmacological potency in going from baboons with the lowest photosensitivity to those with the highest, whereas benzodiazepine receptor occupancy by beta-CCM was similar in the cerebral cortex of the different baboons. Conversely, a given level of convulsant activity of beta-CCM was related to a different benzodiazepine receptor occupancy by the drug, depending on the photosensitivity of Papio papio. A given dose of a drug may, thus, have a different pharmacological potency when occupying the same number of receptors, depending on the physiopathological state of the subject.
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PMID:Relationships between benzodiazepine receptors, impairment of GABAergic transmission and convulsant activity of beta-CCM: a PET study in the baboon Papio papio. 164 49

The rate of occurrence of audiogenic seizures and seizures induced by the benzodiazepine receptor inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM) were analyzed in several recombinant congenic strains of mice bred from B10.D2 and DBA/2J. Although both types of seizures have similar behavioral patterns and might involve GABAergic mechanisms, no correlation was observed between the occurrence of the two types of seizures across the strains, suggesting that these two types of seizures depend on different genetic mechanisms.
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PMID:Analysis of B10.D2 recombinant congenic mouse strains shows that audiogenic and beta-CCM-induced seizures depend on different genetic mechanisms. 173 42

The beta-carbolines, methyl-beta-carboline-3-carboxylate (beta-CCM) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) are known to have pharmacological properties opposite to those of agonistic benzodiazepines. Convulsions induced by these drugs lead to differential patterns, such as clonus, myoclonic or tonic seizures. In 10 different inbred strains of mice we investigated whether the responsiveness to the two drugs was the same, irrespective of the pattern of convulsions. We found the same ranking in the responsiveness of the strains to both drugs in the case of myoclonic seizures. No such correlation could be found for clonus or tonic seizures. Our conclusion is that the same genetic factors determine myoclonic seizures, whereas a plurality of mechanisms underly the other patterns. Thus, myoclonic seizures seem to be the most appropriate index for evaluating the convulsant action of beta-carbolines in genetic experiments.
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PMID:Comparisons between patterns of convulsions induced by two beta-carbolines in 10 inbred strains of mice. 179

The inbred mouse strains BALB/cBy (C) and C57BL/6By (B6) differed significantly in their susceptibility to seizures induced by the benzodiazepine inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM). Following a 5 mg/kg injection of beta-CCM, 74% of C (n = 35) and 13% of B6 (n = 40) mice exhibited a convulsion. No sex difference was found. Analysis of the reciprocal F1s failed to show either maternal environmental and/or heterosomal effects. A genetic analysis of the strain difference in susceptibility to beta-CCM-induced seizures using recombinant inbred strains (RIS) was performed. The strain distribution for the RIS showed a two group partition. Statistical analysis showed that, although a one-segregating-unit model could not be rejected to explain the strain difference in beta-CCM-induced seizures, some of the evidence weakened the one-segregating-unit hypothesis.
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PMID:beta-Carboline-induced seizures in mice: genetic analysis. 256 Feb 11

The effects of 3-methoxycarbonyl- (beta-CCM, Ia), 3-ethoxycarbonyl- (beta-CCE, Ic), 3-propoxycarbonyl- (PrCC, Ie), 3-N-methylcarboxamido- (FG-7142, Ig) beta-carboline and 2-acetyl-3-methoxycarbonyl-1,2-dihydro-beta-carboline (IIa) as well as of their corresponding 9-acetyl derivatives (Ib, Id, If, Ih and IIb) have been studied in rabbits. In addition, the effects of 6,7-dimethoxy-4-ethyl-3-methoxycarbonyl-beta-carboline (DMCM) have also been studied. In in vitro studies, these drugs compete with 3H-diazepam to benzodiazepine (BDZ) receptor in membrane preparations from brain cortex. The values of IC50 are in the nanomolar range without significant differences between the acetyl derivatives and their congeners only compound If shows a 10-fold decrease of the binding capacity in respect to its congener Ie. In the presence of 10(-5) M GABA, a decrease in the binding capacity for DMCM, Ia, Ic and Ig and an increase for If are observed. In vivo studies show that DMCM, Ia, Ib, IIa and IIb elicit three dose-dependent stages of electrocortical changes (trains of slow waves, trains of spike-and-wave complexes and "grand-mal" seizures). Compounds Ic, Id and Ig elicit only the first two stages. Compound Ih elicits only the first stage. While compound Ie does not affect the EEG pattern, its 9-acetyl derivative If induces changes (cortical spindles and disruption of the hippocampal theta waves) characteristic of agonist ligands of BDZ receptor. These findings confirm that the efficacy of compounds DMCM, Ia, Ic, Id, Ig and Ih as inverse agonists of BDZ receptor in the EEG paradigm parallels the reduction of their apparent binding affinity in the presence of GABA. The 9-acetylated compounds may be more inverse agonist in vivo than predicted from the in vitro findings, due to hydrolysis in the plasma.
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PMID:Neuropharmacology of several beta-carboline derivatives and their 9-acetylated esters. In vivo versus in vitro studies in the rabbit. 284 41

Clonic seizures were induced in Swiss or DBA/2 mice by methyl-6-7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), 0.048 mmol/kg i.p., or by methyl-beta-carboline-3-carboxylate (beta-CCM), 0.044 mmol/kg i.p. Measurement of regional brain (cortex, hippocampus, striatum, and cerebellum) amino acid levels after 15 min of seizure activity showed increases in gamma-aminobutyric acid (GABA) (in all regions after beta-CCM, and in cortex and hippocampus after DMCM), and an increase in glycine in the striatum after beta-CCM. Aspartate levels fell (in cortex and hippocampus) after DMCM, but were unchanged in all regions after beta-CCM. Glutamate levels fell in cortex after beta-CCM and in striatum after DMCM. Pretreatment with the excitatory amino acid receptor antagonist, 2-amino-7-phosphonoheptanoic acid, 0.5 mmol/kg i.p., 45 min prior to the beta-carboline, significantly increased the ED50 for DMCM-induced clonic seizures (4.68 mumol/kg vs. 9.39 mumol/kg). Similar pretreatment did not significantly alter the ED50 for beta-CCM (4.22 mumol/kg vs. 6.6 mumol/kg). Pretreatment with 2-amino-7-phosphonoheptanoic acid, 1.0 mmol/kg, blocked the increase in GABA content produced by DMCM but not the fall in cortical aspartate content. Potassium-induced release of preloaded D-[3H]aspartate from rat cortical or hippocampal minislices was enhanced in the presence of DMCM (100 microM). In contrast, stimulated release of D-[3H]aspartate (from cortex or hippocampus) was not altered in the presence of beta-CCM (100 microM). Although DMCM and beta-CCM are both considered to induce convulsion by acting at the GABA--benzodiazepine receptor complex, the convulsions differ in several pharmacological and biochemical respects. It is suggested that enhanced release of excitatory amino acid neurotransmitters plays a more important role in seizures induced by DMCM.
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PMID:Effects of two convulsant beta-carboline derivatives, DMCM and beta-CCM, on regional neurotransmitter amino acid levels and on in vitro D-[3H]aspartate release in rodents. 286 Dec 48

The antagonistic effects of the benzodiazepine receptor inverse agonist beta-CCM (1 mg/kg) and of the partial inverse agonist RO 15-3505 (3 mg/kg) on the anxiolytic properties of ethanol (1 g/kg) in mice confronted with a light/dark choice procedure and with the staircase test were investigated. Both drugs reversed the effects of ethanol on some of the behavioral parameters, but beta-CCM alone elicited anxiogenic intrinsic effects. RO 15-3505 induced seizures in mice treated with a subconvulsant dose of pentylenetetrazole, the most efficient doses being 3 and 6 mg/kg. These data indicate that beta-CCM and RO 15-3505 can reverse some of the anxiolytic effects of ethanol, acting probably to oppose GABA function via the benzodiazepine receptor.
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PMID:The benzodiazepine receptor inverse agonists beta-CCM and RO 15-3505 both reverse the anxiolytic effects of ethanol in mice. 289 86

The electroencephalographic (EEG) effects of inverse benzodiazepine (BDZ) agonists have been studied in rabbits after i.v. administration. A dose-dependent progression of three different stages of EEG changes have been observed with inverse BDZ agonists. At first, trains of slow waves in the occipital cortex occur, followed by trains of spike-and-wave complexes in the sensorimotor cortex. These two stages are superimposed on a desynchronized cortical activity, accompanied by an enhancement of the hippocampal theta rhythm. These EEG changes parallel a state of alertness. The third stage is characterized by generalized grand-mal seizures made up of high voltage spikes in the cortical and subcortical brain areas accompanied by generalized tonico-clonic convulsions. No modification of electrical activity is observed at the level of the spinal cord. Methyl-beta-carboline-3-carboxylate (beta-CCM) (at doses higher than 0.2 mg/kg) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (at doses higher than 0.4 mg/kg) elicit all three stages, whereas ethyl-beta-carboline-3-carboxylate (beta-CCE) (0.2-2 mg/kg) and N-methyl-beta-carboline-3-carboxamide (2-20 mg/kg) only elicit the first two, and finally CGS 8216 only the first. The extent of the EEG progression by inverse BDZ agonists may therefore be used as an index of the efficacy of each compound. The BDZ antagonists Ro 15-1788 and Ro 15-3505 (0.3 mg/kg or higher), which do not change the EEG pattern, block the effects of the convulsant and subconvulsant doses of the inverse BDZ agonists, giving rise to a desynchronized EEG pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Supraspinal convulsions induced by inverse benzodiazepine agonists in rabbits. 298 8

The convulsant actions of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and of methyl beta-carboline-3-carboxylate (beta-CCM) were evaluated in the baboon (Papio papio). DMCM, 0.6-4 mg/kg, induced epileptic seizures with short latency. DMCM convulsive seizures could be blocked by i.v. administration of the benzodiazepine agonist diazepam (10 mg). Similarly, beta-CCM, 0.3-3 mg/kg i.v., provoked generalized seizures in the baboons. These seizures were also reversed by the administration of propyl beta-carboline-3-carboxylate (3 mg/kg) or of diazepam (5 mg/kg). Combining the results from Positron Emission Tomography and the EEG assessments, benzodiazepine receptor occupancy by beta-CCM and DMCM was directly correlated with their convulsant actions in the living baboon. beta-CCM exerted its convulsant action in the living baboon at 76 and 74% benzodiazepine receptor occupancy in, respectively, occipital and temporal cortices whereas DMCM displayed a similar convulsive activity when only 58 and 65% of these receptors in the above regions were occupied.
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PMID:Benzodiazepine receptors studied in living primates by positron emission tomography: inverse agonist interactions. 304 Apr 33

Derivatives of ethyl-beta-carboline-3-carboxylate, ZK 91296, ZK 93423 and ZK 95962 have potent anticonvulsant activity against sound-induced seizures in audiogenic DBA/2 mice and against photically-induced seizures in the baboon, Papio papio. The convulsant beta-carbolines, DMCM and beta-CCM, have proconvulsant and convulsant activity in the same animal models. DMCM and beta-CCM are similar in potency as convulsants in DBA/2 mice (ED50 value for DMCM: 1.3 mg/kg; ED50 value for beta-CCM; 0.8 mg/kg), but differ with respect to their profiles for protection by anticonvulsant drugs. The anticonvulsant potencies of diazepam and clobazam are similar against both types of beta-carboline-induced seizures, whereas quazepam protects better against beta-CCM seizures (4 fold elevation in ED50 value at 1 mg/kg quazepam IP) than against DMCM seizures (1.7 fold elevation in ED50 value), supporting a preferential action of beta-CCM on BZ1 receptors. Valproate (400 mg/kg) and gamma-vinyl-GABA (1.5 g/kg) protect better against beta-CCM seizures (9.5 and 5.9 fold elevations in ED50 values respectively) than against DMCM seizures (1.8 and 2.7 fold elevations in ED50 values respectively). The excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid, has significant anticonvulsant activity against DMCM seizures. The elevated regional GABA levels in brains of DBA/2 mice observed during beta-CCM seizures are eliminated by the pretreatment with Ro 15-1788, which also blocks the seizure activity.
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PMID:Bidirectional effects of beta-carbolines in reflex epilepsy. 311 61


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