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PubMed1994

Effects of diltiazem in convulsive states differ from those previously reported for dihydropyridine calcium channel antagonists.

Unlike the dihydropyridine calcium channel antagonists studied previously, the benzothiazepine calcium channel antagonist, diltiazem, increased the incidence of convulsions caused by bicuculline, N-methyl-DL-aspartate or 4-aminopyridine. However, the latencies to convulsions were also increased. Diltiazem increased the ratings of convulsive behaviour on handling after intraperitoneal administration of bicuculline, or pentylenetetrazol and after the calcium channel activator, Bay K 8644, administered ICV. When the binding of the dihydropyridine, [3H]-nitrendipine in the CNS was measured in vivo, this was increased by diltiazem. This compound therefore showed a different pattern of interaction with convulsant drugs then that previously demonstrated for other calcium channel antagonists, appearing to possess both pro- and anticonvulsant actions, and a different pattern of interaction with the dihydropyridine receptor complex.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Effects of soman-induced convulsions on phosphoinositide metabolism.

Turnover of [3H]phosphoinositides (PI) was examined in brain slices from the hippocampus of rats undergoing soman-induced seizure activity. Hydrolysis of PI was determined by measuring the accumulation of [3H]inositol-1-phosphate (IP1). Incubation of hippocampal slices in the presence of carbachol or norepinephrine (NE) increased PI hydrolysis. Stimulated hydrolysis by NE, but not carbachol was significantly reduced in slices from soman-challenged rats undergoing convulsive activity. NE-stimulated PI hydrolysis was not reduced in slices from animals exposed to soman that did not exhibit convulsive activity. In rats surviving for 24 h, the response to NE was not different from control rats. In control slices, NE-stimulated hydrolysis of PI was potentiated by GABA. No potentiation by GABA was seen in slices from animals undergoing seizures. Uptake and incorporation of myo-[2-3H]inositol into phospholipids was reduced in slices from rats undergoing convulsions. Reduced IP1 production appeared to be owing, in part, to decreased synthesis of inositol lipids. These observations suggest that during soman-induced seizure activity, there is an apparent decrease in the response of the PI second messenger system to NE stimulation, and that this may contribute to the severity and duration of convulsions and brain damage resulting from exposure to soman and other anticholinesterase compounds.

Animals↗
PubMed2003

The influences of extremely low frequency magnetic fields on drug-induced convulsion in mouse.

This study investigated the effects of extremely low frequency magnetic fields (ELF-MFs) on the sensitivity of seizure response to bicuculline, picrotoxin and NMDA in mice. The mice were exposed to either a sham or 20 G ELF-MFs for 24 hours. Convulsants were then administered i.p. at various doses. The seizure induction time and duration were measured and lethal dose (LD50) and convulsant dose (CD50) of the clonic and tonic convulsion were calculated. The analysis of glutamate, glycine, taurine and GABA of mouse brain was accomplished by HPLC. The mice exposed to ELF-MFs showed moderately higher CD50, LD50 and onset time on the bicuculline-induced seizure. However, the ELF-MFs did not influence them in the NMDA and picrotoxin-induced seizures. After the exposure to MFs exposure, the glutamate level was increased and GABA was decreased significantly in NMDA and picrotoxin-induced seizure. The level of glutamate and GABA were not changed by MFs in bicuculline-induced seizure. These results suggest that ELF-MFs may alter the convulsion susceptibility through GABAergic mechanism with the involvement of the level of glutamate and GABA.

Animals↗
PubMed1990

Physiological modulation of the GABA receptor by convulsant and anticonvulsant barbiturates in cultured rat hippocampal neurons.

The actions of convulsant and sedative barbiturates on responses to gamma-aminobutyric acid (GABA) application and on inhibitory postsynaptic currents were compared using voltage-clamp techniques in cultured rat hippocampal neurons. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2-enyl) barbituric acid (3M2B), and (+)-5-ethyl-5-(1,3-dimethylbutyl) barbituric acid [+)-DMBB), and the sedative barbiturate, 5-ethyl-5-(3-methylbutyl) barbituric acid (3MB), all potentiated GABA-mediated chloride currents. In addition, these compounds prolonged the duration of GABAergic inhibitory postsynaptic currents. The similarity between the action of convulsant and sedative barbiturates suggests that the convulsant activity of 3M2B and (+)-DMBB are not mediated by their actions at GABAergic synapses.

Animals↗
PubMed1984

Effects of iontophoretic application of convulsants on the sensory responses of neurons in the brain-stem reticular formation.

Iontophoretic or pneumatic application of convulsants produced enhancement of the sensory responses of brain-stem reticular formation (RF) neurons in cat and rat. Enhanced sensory responsiveness is observed with visual, auditory, somatosensory and vibrissa manipulation following application of strychnine, bicuculline or pentylenetetrazol. The effect was not transmitter-specific, since it could be produced by sequential application of bicuculline and strychnine which are thought to affect different neurotransmitters. Intravenous administration of convulsant also enhanced the responsiveness of RF neurons which had previously been affected by application of a different convulsant. Both systemic and iontophoretic effects could be antagonized by application of GABA and glycine. These data, coupled with previous findings in primary sensory pathways, indicate that sensory response enhancement in the RF induced by intravenous administration of these convulsants is in large part due to actions on synaptic elements of reticular formation neurons.

Animals↗
PubMed1977

Convulsant-anticonvulsant interactions on seizure activity and cortical acetylcholine release.

The effects of leptazol and bicuculline on the efflux of endogenous acetylcholine (ACh) from the surface of the cerebral cortex have been related to EEG activity in urethane-anaesthetised rats. During seizure activity there was a calcium dependent increase in ACh efflux which was related to increase EEG activity and clonic muscle movements. ACh release and EEG activity were reduced during convulsive activity by trimethadione but not phenytoin. Phenobarbitone reduced convulsive EEG activity but left ACh release relatively unaffected. Blood pressure changes induced by convulsant and anticonvulsant drugs were not consistently related to EEG activity or ACh release. It is suggested that ACh efflux from the cerebral cortex is closely related to the activity of neurones within the cortex where it is released from nerve endings. Comparison of EEG changes induced by anticonvulsants and urethane during control and convulsant activity showed that only trimethadione produces anticonvulsant activity unaccompanied by general CNS depression.

Acetylcholine↗
PubMed1979

Convulsant, anticonvulsant and anaesthetic barbiturates. 5-Ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid and related compounds.

Barbiturates derived by minor structural changes to the butenyl sidechain of the convulsant 5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid are almost devoid of convulsant activity, but all have anaesthetic and anticonvulsant effects. Anticonvulsant activity is also observed in the convulsant barbiturate. Increased lipophilic character does not increase anaesthetic potency, only speed of onset, and anticonvulsant activity is reduced in the more lipophilic compounds. The stereochemistry at the 3'-position of the sidechain is vitally important to convulsant activity, and also influences anticonvulsant potency.

Anesthetics↗
PubMed1992

Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice.

Four guanidino compounds that are known to accumulate in uremia, namely creatinine, guanidine, guanidinosuccinic acid and methylguanidine, were administered intraperitoneally and intracerebroventricularly to adult albino mice and the compounds epileptogenic and toxic properties were behaviorally assessed. After intraperitoneal injection, brain concentration of the compounds as a function of injected dose was monitored additionally. Guanidino compound brain concentration was determined by cation exchange chromatography with fluorescence ninhydrin detection. After systemic administration, especially guanidinosuccinic acid and methylguanidine induced long-lasting generalized convulsions which gradually increased in severity. Increasing the dose injected intraperitoneally resulted in linear increase in brain concentration of the injected compounds, in parallel with increase in proportion of animals presenting with convulsions and/or severity of convulsions. Guanidinosuccinic acid brain concentration increased more slowly than that of the other 3 compounds and guanidinosuccinic acid also exerted its effect later than the others. Since none of the other metabolically related guanidino compounds determined was significantly increased in the brains of the injected animals, the observed behavior was most certainly induced by the compounds injected and not by some secondary metabolite. Epileptogenic properties of the four compounds were markedly and qualitatively different in systemic administration, but rather similar in intracerebral administration. A tentative epileptogenic potency order was inferred from the combined behavioral and biochemical results. All 4 of the compounds tested displayed the ability to induce full-blown clonic-tonic convulsions and they did so in a dose-related manner. Guanidinosuccinic acid appeared to be slightly more potent than methylguanidine, but both guanidinosuccinic acid and methylguanidine were considerably more potent than guanidine. Creatinine was many times less potent than the other 3 guanidino compounds. Revised epileptogenic potency order on the basis of guanidino compound brain concentration after systemic administration as well as potency order after intracerebral administration paralleled the potency order of these compounds in their GABA antagonism reported earlier. It was therefore postulated that the GABA antagonism of uremic guanidino compounds could underlie their epileptogenic character. Moreover, these compounds could very likely be at the basis of the neurological complications including epilepsy of uremic patients in whom they accumulate in physiological fluids and brain.

Animals↗
PubMed1983

Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of beta-carboline-3-carboxylic acid esters.

Both the methyl ester of beta-carboline-3-carboxylic acid and the 6,7-dimethoxy-4-ethyl derivative of this compound are potent convulsants in rodents, while the ethyl ester of beta-carboline-3-carboxylic acid does not cause convulsions, even when administered at very high doses. The rate of degradation of these compounds by rat plasma (in vitro) parallels their potencies as convulsants. In contrast, 3-carboethoxy-beta-carboline was found to potently elicit tonic and clonic convulsions in the squirrel monkey (Saimiri sciureus). Furthermore, the rate of degradation of 3-carboethoxy-beta-carboline in monkey plasma (in vitro) is negligible compared with rats. No significant differences were observed in either the potency or efficacy of GABA to inhibit [3H]beta-carboethoxy-beta-carboline binding in rat and monkey brain. These data strongly suggest that pharmacokinetic, as well as pharmacodynamic, factors may determine the pharmacologic profile of these beta-carboline-3-carboxylic acid esters.

Animals↗
PubMed1988

Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs.

The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit [3H]diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe at least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel.

Animals↗
PubMed1982

Convulsant action of intracerebroventricularly administered l-kynurenine sulphate, quinolinic acid and other derivatives of succinic acid, and effects of amino acids: structure-activity relationships.

Succinic acid, and the derivatives which have been tested, i.e. phthalic, l-glutamic, l-aspartic, citric and laevulinic acids, in doses of 5,2,5,20,20 and 50 micrograms, respectively, as well as l-kynurenine sulphate and quinolinic acid, injected into the brain ventricles in mice, induced clonic seizures. When administered intraperitoneally or orally they antagonize strychnine-induced seizures. The convulsant effect of l-kynurenine sulphate was observed only when the pH of the solution was 4.0 or lower, while the actions of the other drugs tested were not dependent upon pH. Control intraventricular injections of 5 microliters of 0.06 N sulphuric acid (equivalent to 16.7 micrograms of SO4(2-), the same dose as was injected when a convulsant dose of 50 micrograms of l-kynurenine was administered) induced seizures in 25% of the mice. It is suggested that the convulsant effect of quinolinic acid and l-kynurenine sulphate is related to a moiety of succinic acid (O = C-C-C-C = O). The effect of l-kynurenine sulphate comprises the action of the cation of kynurenine and that of the anion of sulphuric acid. Reduction of the convulsant effect of l-kynurenine sulphate by alpha-amino acids and taurine is presumably related to a "shielding" of both amino- and carbonyl groups of 1-kynurenine. There is no evidence that l-kynurenine sulphate, in small doses, shares the central effects of the inhibitory amino acids.

Amino Acids↗
PubMed1985

Comparative effects of convulsant drugs on the sensory responses of neurons in the amygdala and brainstem reticular formation.

The sensory responses of neurons in the amygdala and mesencephalic reticular formation in the cat were enhanced following the intravenous administration of subconvulsant doses of bicuculline, strychnine, bemegride, pentylenetetrazol and physostigmine. The degree and intensity of the enhancement of the response was considerably greater in the reticular formation than in the amygdala. The latency of the response in simultaneously-recorded pairs of neurons in the amygdala and reticular formation was significantly shorter in the mesencephalic reticular formation. The enhancement induced by convulsants does not appear to be transmitter-specific, since enhancement was produced with sequential administration of convulsant drugs which affect gamma-aminobutyric acid (GABA), glycine or acetylcholine. These findings suggest that the reticular formation is involved, to a larger degree than the amygdala, in the ability of sensory stimuli to initiate generalized convulsive seizures in animals treated with these convulsant drugs. The enhancement of the response in the hippocampus and cortex, which has previously been shown to exhibit a longer latency and a lower degree of enhancement than the reticular formation, coupled with the findings in the amygdala, suggest that the reticular formation may mediate the enhancement of the response of these other regions of the brain. The spread of the enhancement of the response to other structures in the brain via the widely distributed output pathways from the reticular formation may lead to initiation of generalized seizures by a recruitment-like process, which may involve enlargement of the sensory hyperresponsive neural network of the brain until a critical neural mass is reached and initiation of seizures results.

Amygdala↗
PubMed1978

Differential effects of convulsants on visually evoked responses in the albino rat.

Visually evoked responses (VERs) were recorded from primary visual cortex in unanesthetized albino rats during pharmacological modulation by one of the following convulsant agents: Physostigmine, picrotoxin, strychnine and Metrazol. The data were analyzed in terms of effects on VER components. The rat VER consists of six distinct waves constituted by three positive peaks (P1--P3) and three negative peaks (N1--N3). Results indicate a differential convulsant action on VER components. The administration of picrotoxin, resulted in a suppression of the peak amplitude of P1--N1 and delayed peak latencies of all components. Strychnine reliably shortened P1, N1 and P2 peak latencies, significantly increased N3 peak latency and only suppressed P3--N3 amplitude. Physostigmine essentially suppressed all component amplitudes but only increased peak latencies for P2 and P3 components. Metrazol, in general, was found to be relatively ineffective in the alteration of any VER component in a systematic manner. The data are discussed in terms of differential modes of convulsant action on the visual system. The results are likewise discussed with respect to their implications for convulsant modulation of photically evoked after-discharges.

Animals↗
PubMed1984

Differential interactions of GABA agonists, depressant and convulsant drugs with [35S]-t-butylbicyclophosphorothionate binding sites in cortex and cerebellum.

Effects of three GABA agonists, four GABA antagonists and convulsants (picrotoxinin, alpha-dihydropicrotoxinin [DHP], pentamethylenetetrazole [PTZ] and isopropylbicyclophosphate ester) and three depressant drugs (pentobarbital, (+)etomidate and etazolate) were investigated on [35S]t-butylbicyclophosphorothionate (TBPT) in cortex and cerebellum. All the convulsants tested were equipotent in inhibiting [35S]TBPT binding in cortex and cerebellum. Convulsants like picrotoxinin inhibited [35S]-TBPT binding competitively in both cortex and cerebellum. In contrast, gamma-aminobutyric acid (GABA) agonists (muscimol, GABA and 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol [THIP]), and depressants like etazolate, (+)etomidate and pentobarbital were more potent inhibitors of [35S]TBPT binding in cerebellum than in cortex. GABA inhibition of [35S]TBPT binding appears to be mediated through a low-affinity site. GABA and pentobarbital inhibited [35S]TBPT binding in cortex and cerebellum noncompetitively. Depressants like pentobarbital appear to interact with the TBPT sites allosterically. These results suggest that depressant and convulsant drugs that modulate GABAergic transmission interact differently with the TBPT binding sites in cortex and cerebellum.

Animals↗
PubMed1985

A possible role of a GABAergic mechanism in the convulsant action of RO5-4864.

The purpose of the present investigation was to determine the possible role of GABAergic mechanism in the convulsant action of RO5-4864. Benzodiazepines (BZ) and other agents which facilitate central GABAergic transmission delayed the onset of facial and forelimb clonus, whereas tonic hind limb extension was blocked in a dose-dependent manner. RO5-4864-induced convulsions were blocked by diazepam, clonazepam, pentobarbital, ethanol and amino-oxyacetic acid (AOAA). RO5-4864-induced convulsions were not blocked by the BZ antagonist RO15-1788. Specifically, RO15-1788 caused a decrease in the onset of severity component of tonic seizures, which tended to become generalized and precipitated in a tonic extension of the hindlimbs. Further, subconvulsive doses of a direct GABA receptor antagonist, bicuculline, enhanced the proconvulsant action of RO5-4864, indicating thereby a potential antagonism of the central GABAergic transmission. These observations strongly suggest that RO5-4864 probably elicits convulsions by selective impairment of the GABAergic transmission.

Animals↗
PubMed1992

Anticonvulsant and convulsant effects of organic solvents.

Previous studies suggest that organic solvents show anticonvulsant and convulsant effects, respectively at low and high doses. In the present study the first experiment was designed to determine low and high doses of injected acute n-hexane, ethyl acetate and toluene in mice through LD50 estimations. In the second experiment, high doses (around LD50) were employed to evaluate the convulsant effects. Finally, the third experiment evaluated the ability of low doses to prevent electroshock- and PTZ-induced convulsions. Results showed that n-hexane increased the severity of the electroshock-induced seizures only at low doses and had no anticonvulsant effects. Ethyl acetate produced generalized clonic seizures and deaths at high doses and was ineffective to prevent electroshock- and PTZ-induced seizures at low doses. Toluene induced forelimb clonus at high doses and protected against electroshock-induced seizures at low doses. Therefore, the biphasic property on convulsant activity seems to be a feature not shared among organic solvents.

Acetates↗
PubMed1993

Inhibition of t-[35S]butylbicyclophosphorothionate binding by convulsant agents in primary cultures of cerebellar neurons.

The characteristics of the picrotoxinin binding site present on the gamma-aminobutyric acidA (GABAA) receptor were studied in neurons using primary cultures of cerebellar granule cells. The binding properties of these sites in intact cultured cells were compared with those measured in cultured cell membrane preparations. t-[35S]Butylbicyclophosphorothionate (TBPS) binding was performed in cultured rat cerebellar neurons grown for 13 days. Binding parameters (Kd and Bmax) were similar to those reported in the literature determined using brain membranes. However, equilibrium was reached faster when using intact cultured neurons. Convulsant compounds like picrotoxinin (PTX) and pentylenetetrazol (PTZ) competitively inhibited the binding of TBPS in this in vitro system. Convulsant organochlorine pesticides (gamma-hexachlorocyclohexane gamma-HCH or lindane and the cyclodienes aldrin, endrin, dieldrin and alpha-endosulfan) competitively inhibited [35S]TBPS binding in cerebellar neuronal cultures. Inhibitory affinity constant (Ki) values were in the nanomolar range, alpha-endosulfan and endrin being the most potent inhibitors corresponding to their high toxicity in mammals. Stereospecificity was also shown for HCH isomers, the non-convulsant isomers (alpha- and delta-HCH) being 15-30 times less potent in inhibiting [35S]TBPS binding than the convulsant gamma-HCH, while the beta-isomer was inactive.

Animals↗
PubMed2006

Mapping convulsants' binding to the GABA-A receptor chloride ionophore: a proposed model for channel binding sites.

Gamma-aminobutyric acid (GABA) type A receptors play a key role in brain inhibitory neurotransmission, and are ligand-activated chloride channels blocked by numerous convulsant ligands. Here we summarize data on binding of picrotoxin, tetrazoles, beta-lactams, bicyclophosphates, butyrolactones and neurotoxic pesticides to GABA-A ionophore, and discuss functional and structural overlapping of their binding sites. The paper reviews data on convulsants' binding sensitivity to different point mutations in ionophore-lining second trans-membrane domains of GABA-A subunits, and maps possible location of convulsants' sites within the chloride ionophore. We also discuss data on inhibition of glycine, glutamate, serotonin (5-HT3) and N-acetylcholine receptors by GABA-A channel blockers, and examine the applicability of this model to other homologous ionotropic receptors. Positioning various convulsant-binding sites within ionophore of GABA-A receptors, this model enables a better understanding of complex architectonics of ionotropic receptors, and may be used for developing new channel-modulating drugs.

Animals↗