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PubMed1996

Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs.

Group III metabotropic glutamate receptors (mGluR4, 6, 7, 8) are negatively coupled to adenylate cyclase and, when activated presynaptically, decrease the release of glutamate and GABA. We have used intracerebroventricular injections of agonists and antagonists believed to act selectively on these receptors to study the pro- or anti-convulsant effects of mGluR III activation in nonepileptic (Swiss-Webster) and epileptic (DBA/2) mice. In both mouse strains the prototypic agonists L-2-amino-4-phosphonobutanoate (LAP4) and L-serine-O-phosphate are proconvulsant. The supposed antagonists (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), have a predominantly proconvulsant effect. (S)-alpha-methyl-3-carboxyphenylalanine, which is a potent and selective antagonist for LAP4 in the cortex, is anticonvulsant in DBA/2 mice and decreases the convulsant effect of N-methyl-D-aspartate, 3,5-dihydroxyphenylglycine, LAP4 and MPPG in Swiss-Webster mice. These data suggest that reduced inhibitory transmission may be more significant than reduced synaptic release of glutamate following group III mGluR activation.

Acoustic Stimulation↗
PubMed1985

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.

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.

2-Amino-5-phosphonovalerate↗
PubMed1976

Effects of amino acids and convulsants on spontaneous action potentials in cerebellar cortex slices.

1 Picrotoxin selectively and reversibly suppressed the inhibitory action of gamma-aminobutyric acid (GABA), but not that of glycine, taurine or beta-alanine, on the frequency of spontaneous spike discharges in guinea-pig cerebellar slices. Strychnine reversibly suppressed the inhibitory action of glycine, taurine or beta-alanine but had no effect on that of GABA. 2 GABA, glycine, taurine and beta-alanine showed an early excitatory effect that was unaffected by picrotoxin or strychnine. 3 Studies of the dose-response relations indicated a competition between the amino acid and the convulsant at a common receptor site. 4 Kinetic analyses of the dose-response relations for the amino acids in the presence or absence of picrotoxin or strychnine indicated that the number of molecules of amino acid combining with the receptor site in order to produce a response (inhibition or excitation) was 3 for GABA, 2 for glycine, 3 for taurine and 4 for beta-alanine. There appeared to be no evidence that the response was due to the cooperativity between the amino acid receptor complexes. The number of molecules of convulsant that combined with the receptor site was 1 for either strychnine or picrotoxin. 5 Mixtures of glycine with taurine or beta-alanine, in contrast to those with GABA, appeared not to give additive inhibitory effects.

Action Potentials↗
PubMed1981

Convulsant and possible anticholinergic actions of dendrotoxin in the amphibian spinal cord.

1 Dendrotoxin (DTOX)6, 6a and 5,6-1, fractions of the venom isolated from the green mamba (Dendroaspis viridis) promoted both spontaneous and stimulus-coupled rhythmic activity and antagonized the cholinergically mediated ventral root-dorsal root potential (VR-DRP) of frog spinal cord. The different time course and reversibility of these two effects indicates that the toxin has two entirely separate sites of action on the frog spinal cord. 2 Since DTOX 6 neither blocked nor enhanced responses of ventral and dorsal roots to glutamate, gamma-aminobutyric acid (GABA), beta-alanine, glycine or aspartate, it is unlikely that its convulsant action resulted from an alteration of the postsynaptic actions of inhibitory or excitatory amino acids. 3 An alteration in the threshold for action potential generation could perhaps contribute to the convulsant action of DTOX 6, although other mechanisms such as blockade of the release of unspecified inhibitory substances cannot be excluded. 4 In addition to the lack of effect on amino acid responses, DTOX failed to block the polysynaptic DR-VRP or DR-DRP pathways, which are mediated at least in part by amino acid neurotransmitters. Although this would be consistent with a specific action of DTOX at the cholinergic synapse of the VR-DRP pathway, this site of action has not yet been demonstrated unequivocally. Other possible mechanisms whereby DTOX could block VR-DRP are discussed.

Animals↗
PubMed1984

Pro- and anti-convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance.

Ro 5-4864 is a benzodiazepine that differs from diazepam only in a p-chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [3H]-Ro 5-4864 from its binding sites. PK 11195 (30-60 mg kg-1) significantly reduced the incidence of convulsions caused by Ro 5-4864 (30 mg kg-1). PK 11195 (up to 120 mg kg-1) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5-3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg-1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored. PK 11195 (30-90 mg kg-1) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole. No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg-1) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg-1) with picrotoxin (3 mg kg-1). There was no cross-tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies. The possible sites of action and clinical relevance of these effects are discussed.

Animals↗
PubMed1988

Interactions of the imidazodiazepine Ro 15-4513 with chemical convulsants.

1. The proconvulsant effects of the imidazodiazepine Ro 15-4513, were investigated in mice by use of intravenous infusion of a variety of convulsant drugs. 2. Dose-response and time course studies of Ro 15-4513 against gamma-aminobutyric acid (GABA) antagonists were performed. On the basis of these studies a maximally effective dose of 5 mg kg-1 was administered 5 min before the determination of seizure thresholds in subsequent experiments. 3. Ro 15-4513 (5 mg kg-1) significantly lowered seizure thresholds to pentylenetetrazole, bicuculline and the convulsant benzodiazepine Ro 5-3663, but failed to alter seizure thresholds to picrotoxin, strychnine, caffeine and quipazine. 4. Ro 15-4513 significantly raised seizure threshold to the benzodiazepine receptor inverse agonist methyl 6,7-dimethoxy-4 ethyl-beta-carboline-3-carboxylate (DMCM). 5. These results are discussed in relation to other studies investigating the proconvulsant and alcohol-antagonizing effects of Ro 15-4513.

Animals↗
PubMedDate not supplied

Seizure susceptibility in DBA and C57 mice: the effects of various convulsants.

Convulsive dose 50s (CD50s) for various convulsive drugs and minimal and maximal electroshock seizure thresholds were determined in DBA and C57 mice. DBA mice had lower maximal electroshock seizure thresholds (MESTs, 15%) and CD50s for homocysteine thiolactone (HTL, 23%) and bicuculline (69%), and a higher CD50 for pentylenetetrazol (PTZ) at 3 weeks of age, the age of maximal audiogenic seizure (AGS) susceptibility. At 8 weeks, when DBA mice are not susceptible to AGSs, significant differences were a lower minimal electroshock seizure threshold (mEST, 37%) and maximal EST (MEST) (19%), lower CD50s for N-methyl-D-aspartate (NMDA) (39%), kainic acid (KA, 50%), HTL (32%), strychnine (37%), and a higher CD50 for nicotine (55%) in DBA mice. Based on these data it is suggested that pathways involving NMDA and KA receptors are responsible for increased susceptibility to seizure initiation (mEST), and are opposed by glycine pathways, and that opposing GABA and cholinergic systems at higher CNS levels are involved in seizure spread (AGSs and MEST) in these mice. Latency patterns indicate that nicotine, strychnine, PTZ and bicuculline have high blood-brain barrier (BBB) penetrability. Picrotoxin and the excitatory amino acid receptor agonists had longer latencies, suggesting low BBB penetrability. Age-related changes in latency, however, give evidence that difficulty in drug penetration of the BBB is not responsible for differences observed in CD50s between strains.

Acoustic Stimulation↗
PubMedDate not supplied

Convulsions induced by methyl beta-carboline-3-carboxylate in mice: effects of preceding saline injections.

The convulsant effects of a high (5 mg/kg intraperitoneally, i.p.) dose of benzodiazepine (BZD) receptor ligand methyl beta-carboline-3-carboxylate (beta-CCM), whether or not preceded by administration of two lower doses of beta-CCM (0.5 and 1 mg/kg i.p.) or of saline were studied in nine inbred mouse strains. In five of the strains (A/J, BALB/cBy, C3H/HeJ, CBA/H, and DBA/2J), neither saline nor preceding injections of beta-CCM had any effect on subsequent reactivity to the subsequent convulsant dose. In the other 4 strains, such injections induced either tolerance (CPB-K, NZB), or sensitization (C57BL/6J, XLII), whatever the compound subsequently administered (beta-CCM or saline). In these strains, the data rule out any tolerance or sensitization effect due to beta-CCM, but suggest that such effects could be due to injection itself.

Animals↗
PubMed1995

Different postnatal development of convulsions and lethality induced by strychnine in rats.

The convulsant action of strychnine was studied in 310 male albino rats, aged 3 to 25 days. Doses of 0.25-4 mg/kg were administered intraperitoneally and the animals were observed for 30 min. Generalized tonic-clonic seizures involving also tonic hindlimb extension occurred in all age groups. The convulsant effects of strychnine increased from day 3 to day 18, and decreased again from day 25, as indicated by the incidence and latencies of seizures. Lethal effects did not occur before day 12. Hyperactivity was seen as the first sign of strychnine action in rats during the first week of life, automatisms predominating in 18-day-old animals. Electroencephalographic study in 30 rat pups with implanted electrodes demonstrated an extremely poor electro-clinical correlation.

Aging↗
PubMed1995

Comparative convulsant potencies of two carbapenem derivatives in C57 and DBA/2 mice.

The behavioural and convulsant effects of imipenem and meropenem were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizure, and in C57 mice, a strain not prone to seizure. DBA/2 mice were more susceptible than C57 mice to seizures induced by imipenem-cilastatin or meropenem. Imipenem was also 1.9 times more potent than meropenem in inducing clonus in DBA/2 mice. To investigate the possibility that the seizure-inducing activity of imipenem might be due to a probenecid-like effect of cilastatin, animals were treated with imipenem alone. No significant differences were observed between imipenem-cilastatin and imipenem-treated animals. Thus, it is reasonable to exclude a probenecid-like effect of cilastatin. Although the main mechanism for seizure-like activity of imipenem cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of imipenem from the CNS may be postulated. Cilastatin did not induce seizures. In addition, meropenem, a compound structurally related to imipenem, showed weak or no convulsant effects.

Animals↗
PubMed1995

Electrophysiological and metabolic effects of a convulsant barbiturate on dissociated mouse primary sensory neurons.

1. The convulsant barbiturate 5-(2-cyclohexylidene-ethyl)-5-ethyl barbituric acid (CHEB) depolarizes dorsal root ganglion (DRG) neurons. We have applied microfluorimetric and whole-cell patch clamp techniques to investigate the mechanisms underlying this response in freshly dissociated mouse DRG cells. 2. Application of CHEB (2-200 microM) raised cytosolic calcium concentration ([Ca2+]i) rapidly and reversibly in 55% of eighty-three neurons tested. This population did not correlate with other classifications of sensory neurons based on either cell size or the expression of membrane currents. 3. The response was dependent on external calcium and was reduced by 81 +/- 22% by Ruthenium Red. A rise in [Ca2+]i was still seen with the membrane potential clamped at -70 mV, excluding membrane depolarization and activation of voltage-dependent Ca2+ channels as the principal mechanism for the response. 4. The rise in [Ca2+]i was associated with an increase in membrane conductance and a current, ICHEB, which was inward at -70 mV. Both the rise in [Ca2+]i and the current showed 'run-down' under whole-cell recording conditions. When K+ conductances were blocked, the reversal potential of ICHEB was close to 0 mV. This was independent of the Cl- reversal potential, suggesting that ICHEB is carried as a non-specific cation current. 5. In contrast to the change in [Ca2+]i, ICHEB was not dependent on external Ca2+ and the current was still seen when [Ca2+]i as strongly buffered by the pipette filling solution. These data suggest that CHEB opens a non-selective cation channel permeant to Ca2+, raising [Ca2+]i and further depolarizing the cell membrane potential. The exact nature of this conductance remains unknown. These actions could readily account for the convulsant actions of the drug, depolarizing neurons and increasing transmitter release. 6. It was also noted that CHEB increases autofluorescence derived from mitochondrial NAD(P)H. Further examination of this phenomenon using the dye rhodamine 123 to follow changes in mitochondrial potential (psi m) suggested that CHEB is a potent inhibitor of mitochondrial respiration, probably acting at complex I. These effects appeared to be quite distinct from the action of CHEB at the level of the plasma membrane.

Animals↗
PubMed1984

Meduna and the origins of convulsive therapy.

Convulsive therapy for dementia praecox was first used by the Hungarian neuropsychiatrist Ladislas Meduna in January 1934. On the 50th anniversary the author discusses the introduction of the treatment, the role of a theory of the biological antagonism between epilepsy and schizophrenia, and the contributions of Meduna, Sakel, Cerletti, and Bini. He also describes the changes in usage and methods and the impact of psychotropic drugs on the practice of convulsive therapy.

Antipsychotic Agents↗
PubMed2003

Thin layer chromatography convulsant screen extended by gas chromatography-mass spectrometry.

Acute onset convulsive disorders in the canine may result from exposure to a variety of toxicants including strychnine, insecticides, metaldehyde, zinc phosphide, methylxanthines, drugs of abuse, bromethalin, and the tremorgenic mycotoxins (roquefortine and penitrem A). Although several of the above can be identified in a single gas chromatography-mass spectrometry (GC-MS) screen most have to be determined by separate tests. This report describes a modification of the strychnine extraction procedure, which allows thin layer chromatographic (TLC) identification of strychnine, bromethalin, roquefortine, and penitrem A in suspect baits, stomach contents or vomitus, and extends the identification to a wide variety of drugs, pesticides, and environmental contaminants by GC-MS. Samples were mixed with base, extracted into CH2Cl2 and the organic fraction back-extracted with acid. The organic fraction (neutrals) was purified by gel permeation chromatography (GPC) and analyzed by TLC to determine penitrem A and bromethalin. The acidic aqueous fraction was adjusted to pH > 9 and extracted into CH2Cl2. The resulting CH2Cl2 layer (bases) was then analyzed by TLC to determine strychnine and roquefortine. The organic basic and neutral fractions were recombined with a late eluting GPC fraction and analyzed by GC-MS. Of 312 samples analyzed by TLC from 1995 to 2001, 35 were positive for strychnine alone, 58 were positive for both roquefortine and penitrem A, 4 were positive for roquefortine alone, and 1 was positive for bromethalin. None of the samples were positive for penitrem A alone. Samples negative by TLC were analyzed by the GC-MS extended procedure since mid-1999, and 14 have shown positive for a wide variety of compounds with convulsant activity.

Animals↗
PubMed2002

New convulsive compounds, brasiliamides A and B, from Penicillium brasilianum batista JV-379.

New convulsive compounds, brasiliamides A (1) and B (2), were isolated by activity-guided fractionation from okara fermented with a soil isolate of Penicillium brasilianum Batista JV-379. Their structures were elucidated on the basis of spectral and chemical evidence and by X-ray crystallography of the hydrogenated product of 2. In the 1H- and 13C-NMR spectra of 2, the signals were complicated, all being doubled or broadened in several deuterated solvents at room temperature. The conformational change of 2 was clarified as the rotational isomerization of amide bonds in solution by NMR measurements at various temperatures. Four rotamers of 2 at two amide bonds were presented at -60 degrees C in CDCl3, whereas only two isomers were apparent at room temperature, owing to rapid rotation of one of the amide bonds. Brasiliamides A and B respectively showed convulsive activity against silkworms with ED50 values of 300 and 50 microg/g of diet.

Animals↗
PubMedDate not supplied

Effect of adenosine receptor agonists on neurodegenerative and convulsive activity of mitochondrial toxin, 3-nitropropionic acid.

3-Nitropropionic acid (3-NPA) is a mitochondrial toxin inhibiting the activity of succinate dehydrogenase. Its experimental application in rodents causes lesions of the striatum resembling the course of Huntington's disease in humans. Recently, we have shown that 3-NPA is also a potent convulsive and proconvulsive agent. This study investigated the effects of adenosine receptor agonists on neurodegeneration and convulsions induced by 3-NPA. Adenosinergic agonists prevented seizures but not striatal neuronal loss evoked by 3-NPA, what suggests that different mechanisms might contribute to these pathologies associated with application of mitochondrial toxin.

2-Chloroadenosine↗
PubMedDate not supplied

[Revival of convulsive therapy].

After a brief review of the history of convulsive therapy, the paper criticises the denigratory campaign which was directed against this form of therapy for many years in Italy and later abroad. It stresses that convulsive therapy is now used worldwide, in spite of a few justifiable restrictions, for these indications and that the risks involved in the therapy itself, which are minimum, have been reduced. The Authors complain that this revival, which is now spreading internationally, has been hardly felt in Italy, especially in university circles.

Convulsive Therapy↗
PubMedDate not supplied

Effects of some convulsant agents on the protective activity of topiramate against maximal electroshock-induced seizures in mice.

The anticonvulsant activity of topiramate combined with some convulsant agents (bicuculline--BIC, N-methyl-D-aspartate--NMDA, and kainic acid--KA), given at subconvulsive doses, was evaluated in the maximal electroshock (MES)-test in mice. BIC (1.5 mg/kg), KA (10 mg/kg) and NMDA (50 mg/kg) significantly decreased the anticonvulsant activity of topiramate raising its ED(50) from 76.2 mg/kg to 135, 102, and 107 mg/kg, respectively. BIC (0.75 mg/kg) and KA (5 mg/kg) did not alter the protective activity of topiramate in the MES-test. Moreover, topiramate injected alone (up to 135 mg/kg) did not affect motor performance and long-term memory of animals tested in the chimney and passive avoidance tests, respectively. In contrast, combinations of topiramate with BIC (1.5 mg/kg), NMDA (50 mg/kg) or KA (10 mg/kg) considerably disturbed long-term memory in mice. Additionally, co-administration of topiramate with KA (10 mg/kg) or BIC (1.5 mg/kg) significantly impaired motor performance, whereas topiramate co-administered with NMDA (50 mg/kg) had no impact on motor coordination in mice. None of the studied convulsants affected the free plasma concentration of topiramate assayed with immunofluorescence method. The results of this study seem to indicate the expression of the anticonvulsant activity of topiramate is dependent on all ionotropic glutamate and GABAA receptor-mediated events.

Animals↗