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PubMed1996

Increasing-current electroshock seizure test: a new method for assessment of anti- and pro-convulsant activities of drugs in mice.

We developed the increasing-current electroshock seizure (ICES) test, a new method for assessment of anti- and pro-convulsant activities of drugs in mice. In this method, a single train of pulses (square wave, 5 msec, 20 Hz) of linearly increasing intensity from 5 to 30 mA (increment of 0.1 mA/0.1 sec, i.e., 5-30 mA in 25 sec) was applied via ear electrodes. The current at which tonic hindlimb extension occurred was recorded as the seizure threshold. Thus, this method allows determination of the seizure threshold current for individual animals. Carbamazepine, phenytoin, valproate, phenobarbital, diazepam, and morphine all increased the seizure threshold current in a dose-dependent manner, whereas ethosuximide was not effective. The seizure threshold current decreased after treatment with reserpine, chlorpromazine, aminophylline, strychnine, pentylenetetrazol, bicuculline, picrotoxin, and ethyl-beta-carboline-3-carboxylate (beta-CCE). These results indicate that the ICES test, like the maximal electroshock seizure test, is a model of grand mal-type seizure and is useful for evaluation of both the anti- and pro-convulsant activities of drugs.

Analgesics, Opioid↗
PubMed2005

Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors.

GABA(A) receptors mediate most of the fast inhibitory neurotransmission in the brain. Prolonged occupancy of these receptors by ligands leads to regulatory changes often resulting in reduction of receptor function. The mechanism of these changes is still unknown. In this study, stably transfected human embryonic kidney (HEK) 293 cells were used as a model to study the effects of prolonged flumazenil (antagonist of benzodiazepine binding sites at GABA(A) receptors) exposure on the recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors, the most common type of GABA(A) receptors found in the brain. Exposure (48 h) of HEK 293 cells stably expressing recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors to flumazenil (1 or 5 microM) in the presence of GABA (1 microM), enhanced the maximum number (B(max)) without affecting the affinity (K(d)) of [(3)H]TBOB labeled binding sites for convulsants. Diazepam (1 nM-1 mM) in the presence of GABA (1 microM) modulated [(3)H]TBOB binding to control and flumazenil pretreated cells according to a two-site model. No significant differences between the groups were observed in either the potency or efficacy of diazepam to modulate [(3)H]TBOB binding, as evidenced by a lack of significant changes between their IC(50) and I(max) values. The results suggest that chronic exposure of HEK 293 cells stably expressing recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors to flumazenil up-regulates the binding sites for convulsants, but it does not appear to affect the functional coupling between these sites and benzodiazepine binding sites. Along with our recent data, these results suggest that chronic treatment with flumazenil enhances the number of GABA(A) receptors.

Binding Sites↗
PubMed1997

Co-variation of free amino acids in brain interstitial fluid during pentylenetetrazole-induced convulsive status epilepticus.

Effects of pentylenetetrazole (PTZ)-induced convulsive status epilepticus on free amino acids changes in venous blood, CSF and interstitial fluid (IF) of the brain were examined in dogs. A volume of brain IF sufficient for analysis was obtained by chronically implanted tissue cages. The onset of PTZ-induced convulsive seizures seemed mainly related to a marked increase of glutamate, aspartate, taurine, glycine and phosphoserine while, the maintenance and frequency of seizures seemed related to a marked increase of serine and glycine, in combination with a moderate rise of glutamate. L-alpha-Aminoadipate was recovered in moderate amount in epileptic brain IF, while, in controls, this compound was present in minimal amount. The observed complex temporal variation of the amino acidic pattern may play a role in PTZ-induced seizures and, possibly, in pharmacological kindling and brain structural alterations induced by PTZ.

Amino Acids↗
PubMed1997

Role of cerebral spermidine in the development of sensitization to convulsant activity of cocaine and lidocaine.

We have previously shown that daily treatment with subconvulsant dose of cocaine resulted in the elevation of brain levels of polyamines such as putrescine and spermidine and the development of increased susceptibility to cocaine-induced seizures. The present study examined whether exogenously administered polyamines affect seizure activity caused by various doses of cocaine and lidocaine in mice. Thirty minutes after intracerebroventricular treatments with either saline, putrescine or spermidine (1-4 mumol), animals were injected intraperitoneally with cocaine or lidocaine (60-90 mg/kg); then the occurrence of clonic seizures was observed. Spermidine enhanced cocaine-induced seizure activity, while putrescine had no effect on it. Lidocaine-induced convulsions were also dose-dependently potentiated by spermidine. In addition, spermidine significantly enhanced seizure activity following an injection of N-methyl-DL-aspartate. The results suggest that spermidine plays an important role in the development of sensitization to convulsant activity by cocaine and lidocaine via modulation of N-methyl-D-aspartate receptors.

Animals↗
PubMed1998

Pharmacological evidence for GABAergic and glutamatergic involvement in the convulsant and behavioral effects of glutaric acid.

The effect of intrastriatal administration of glutaric acid (GTR), a metabolite that accumulates in glutaric acidemia type I (GA-I), on the behavior of adult male rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of GTR buffered to pH 7.4 with NaOH or NaCl. GTR induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior was prevented by intrastriatal preadministration of DNQX and muscimol, but not by the preadministration of MK-801. Convulsions were prevented by intrastriatal preinjection of muscimol. This study provides evidence for a participation of glutamatergic non-NMDA and GABAergic mechanisms in the GTR-induced behavioral alterations. These findings may be of value in understanding the physiopathology of the neurological dysfunction in glutaric acidemia.

Animals↗
PubMed2002

Characterization of the interaction between a novel convulsant agent, norbiphen, and GABA(A) and other ligand-gated ion channels.

A hybrid molecule composed of the antimicrobial, norfloxacin, linked to the non-steroidal anti-inflammatory drug (NSAID), biphenylacetic acid, which we have termed norbiphen, is a lethal convulsant in vivo and an antagonist of rodent GABA(A) receptors in vitro. In the present study, the selectivity, molecular site(s) and mechanism of action of this novel convulsant were investigated using electrophysiological techniques. Sub-maximal GABA-evoked currents recorded from rodent hippocampal neurons were reversibly inhibited by norbiphen (1 microM) to 5+/-2% of control whereas glutamate, NMDA and glycine activated responses were little or unaffected. Sub-maximal GABA-evoked currents recorded from oocytes expressing recombinant human alpha1beta2gamma2s or alpha1beta2 GABA(A) receptors were also reversibly inhibited by norbiphen (1-1000 nM) with an IC(50) (+/-s.e.m.) of 5.7+/-1 and 8.8+/-1 nM, respectively. Similarly, GABA currents recorded from alpha1beta1gamma2s, alpha1beta1 and beta2gamma2s receptors were inhibited with IC(50)s of 16.1+/-1, 18.8+/-1 and 4.2+/-1 nM, respectively. In contrast, norbiphen (100 nM) had little or no effect at rho1 GABA(C) homomers. At alpha1beta2gamma2s receptors, norbiphen had no affect on the GABA reversal potential, and inhibition was not voltage-dependent, suggesting that this compound does not act at the ion channel. The GABA concentration response curve was shifted in a competitive-like fashion by norbiphen (10-300 nM) and a Schild analysis of these data yielded a slope of 0.94+/-0.1 and a pA(2) of 7.77. Our data reveal a novel, selective and highly potent antagonist of GABA(A) receptors. Norbiphen should be a valuable agent in future studies of this receptor complex.

Animals↗
PubMed2003

Differential sensitivity of genetically Fast vs. Slow kindling rats strains to GABAergic convulsive agents.

Following selective breeding for seizure-proneness vs. seizure-resistance to amygdala kindling, two strains of rats were developed with non-overlapping kindling rates, i.e. the number of stimulations required to develop fully generalized convulsive seizures (Epilepsy Res. 35 (1999) 183). In the temporal cortices of these two strains, the local seizure thresholds to electrical stimulation have been reported to be approximately two times lower in the seizure-prone (Fast kindling) compared to the seizure-resistant (Slow kindling) strain (McIntyre et al., 1999). In the present experiment, the pharmacological sensitivities of the two strains to three GABAergic antagonists, pentylenetetrazol, bicuculline and picrotoxin, were determined, and compared to the glycine antagonist, strychnine. Paralleling kindling epileptogenesis, naïve rats of the Fast kindling strain developed convulsive seizures to doses of the GABAergic antagonists that were significantly (approximately 30%) lower than the naïve Slow kindling strain. In contrast, there were no strain differences in their response to strychnine. These data indicate substantial GABAergic sensitivity differences between the two strains with an emphasis on forebrain mechanisms, which is consistent with other physiological and molecular data related to their differential profiles of epileptogenesis.

Animals↗
PubMed2000

Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate.

A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone, is a 3beta-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

Animals↗
PubMed2003

Convulsant actions of calycanthine.

The principal alkaloid of the family Calycanthaceae, calycanthine has long been recognized as a central convulsant. The alkaloid inhibited the potassium-stimulated release of [(3)H]GABA from slices of rat hippocampus with an ED(50) of approximately 21 microM. This effect appeared to be moderately selective since calycanthine at 100 microM had only a weak effect on the potassium-stimulated release of [(3)H]acetylcholine (15%) and no significant effects on the release of [(3)H]D-aspartate from hippocampal and cerebellar slices or the release of [(3)H]glycine from spinal cord slices. Calycanthine blocked the L-type calcium currents with an IC(50) of approximately 42 microM and also weakly inhibited the N-type calcium currents (IC(50) > 100 microM) from neuroblastoma X glioma cells, suggesting voltage-dependent calcium channel blockade as a possible mechanism for its inhibition of GABA and ACh release. Calycanthine was also found to directly inhibit GABA-mediated currents (K(B) approximately 135 microM) from human alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes but had no effect at 100 microM on human rho(1) GABA(c) receptors. The results indicated that calycanthine may mediate its convulsant action predominantly by inhibiting the release of the inhibitory neurotransmitter GABA as a result of interactions with L-type Ca(2+) channels and by inhibiting GABA-mediated chloride currents at GABA(A) receptors.

Acetylcholine↗
PubMed1986

Alkyl-substituted thiolo-, thiono-, and dithio-gamma-butyrolactones: new classes of convulsant and anticonvulsant agents.

A series of sulfur-containing congeners have been prepared from alpha-ethyl-alpha-methyl-gamma-butyrolactone, beta-ethyl-beta-methyl-gamma-butyrolactone, and alpha,alpha,beta,beta-tetramethyl-gamma-butyrolactone as potential neuropharmacologic agents. The lactones were treated with benzyl mercaptide anion to form 4-(benzylthio)butyric acid, which, on treatment with trifluoroacetic acid, cyclized to yield thiololactones. The thiono- and dithiolactones were prepared by treating the corresponding lactones either with Lawesson's reagent or with phosphorus pentasulfide, respectively. As had been observed previously for the lactones, the beta-substituted and alpha,beta-substituted congeners were potent convulsants that caused generalized clonic and tonic seizures in mice. The alpha-substituted congeners were effective in inhibiting pentylenetetrazole-induced seizures in mice. alpha-Ethyl-alpha-methylthiolo-gamma-butyrolactone showed an increase in potency over the congeneric alpha-ethyl-alpha-methyl-gamma-butyrolactone and, additionally, was effective against maximal electroshock seizures. In no cases was a convulsant converted to an anticonvulsant or vice versa by sulfur-for-oxygen substitution.

4-Butyrolactone↗
PubMed1986

Involvement of neuronal acceptors for dendrotoxin in its convulsive action in rat brain.

Dendrotoxin, a snake-venom polypeptide, is a potent convulsant that facilitates transmitter release apparently by inhibition of voltage-sensitive K+ channels responsible for A-currents. A biologically active 125I-iodinated derivative of this toxin was prepared and used to characterize kinetically homogeneous non-interacting high-affinity acceptors in synaptic membranes from rat cerebral cortex and hippocampus. Binding of radiolabelled toxin from Dendroaspis angusticeps to its membrane acceptor protein was inhibitable by homologous polypeptides from other mamba snakes; most importantly, their rank order of potency was identical with that for their central neurotoxicities in rats, furnishing evidence for involvement of this binding component in the convulsive symptoms observed. Beta-Bungarotoxin, a presynaptically acting neurotoxin whose action on neurotransmitter release at the neuromuscular junction and effects on brain synaptosomes are antagonized by dendrotoxin, was only able to inhibit the binding of the 125I-labelled toxin with low efficacy, although dendrotoxin apparently interacts avidly with the acceptor sites for beta-bungarotoxin. This weak interaction of beta-bungarotoxin with the acceptor was not attributable to its phospholipolytic action. Other neurotoxins and ion-channel antagonists failed to affect the binding of dendrotoxin. The findings presented here, together with recent electrophysiological data, favour the interpretation that dendrotoxin binds to a membrane protein comprising, or closely associated with, this one group of voltage-dependent K+ channels.

Animals↗
PubMed1995

Regulation of c-fos expression by convulsants and hexachlorocyclohexane isomers in primary cultures of cortical neurons.

Primary cortical cultures were used to study the effects of four convulsants on c-fos expression. Approximately 30% of the neurons in these cultures displayed c-fos nuclear immunostaining under basal conditions. The addition of tetrodotoxin, nifedipine, or delta-hexachlorocyclohexane produced a significant decrease in c-fos basal values. Lindane (gamma-hexachlorocyclohexane), Bay K 8644, pentylenetetrazole, and picrotoxinin produced a significant increase in c-fos immunoreactivity and in c-fos mRNA expression. Treatment of cells with tetrodotoxin before administration of the convulsant agents lowered c-fos staining below basal levels. In contrast, delta-hexachlorocyclohexane or nifedipine failed to block only the picrotoxin-induced increase. The differential pattern of expression shown by c-fos after these treatments suggests various mechanisms of action for the compounds studied. The results obtained with delta-hexachlorocyclohexane and nifedipine suggest that picrotoxinin activates c-fos expression by calcium-requiring intracellular signaling pathways that are different from those activated by Bay K 8644, pentylenetetrazole, or gamma-hexachlorocyclohexane, which, at least in part, act via L-type calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1979

Regulation of the state of phosphorylation of specific neuronal proteins in mouse brain by in vivo administration of anesthetic and convulsant agents.

The effect of drug treatment in vivo on the state of phosphorylation of two specific neuronal proteins, proteins Ia and Ib, has been studied in mouse brain. For this purpose, animals were killed by immersion into liquid nitrogen, and proteins Ia and Ib were extracted by a procedure designed to prevent alterations in their state of phosphorylation. Several anesthetic agents (pentobarbital, chloral hydrate, and urethane) each caused a decrease in the state of phosphorylation of these proteins. Conversely, the convulsant agents pentylenetetrazol and picrotoxin each caused an increase in the state of phosphorylation of these proteins. Neither the anesthetic nor the convulsant agents affected the total amount of these proteins. The results are compatible with a role for proteins Ia and Ib in neuronal function.

Anesthetics↗
PubMed1988

Anticonvulsive and convulsive effects of lidocaine: comparison with those of phenytoin, and implications for mechanism of action concepts.

The anticonvulsive action of lidocaine was tested in mice against a series of convulsants, and its profile of action compared with that of phenytoin. Both agents antagonized seizures induced by ouabain or glutamate (injected i.c.b.), effects attributable to reduction of the sodium conductance of neuronal membranes. Lidocaine and phenytoin were relatively ineffective against convulsants that act on synaptic chloride channels via the GABA-ionophore receptor complex. At higher dose levels, both lidocaine and phenytoin are excitatory within limited ranges. Lidocaine-induced seizures were potentiated by phenytoin, and antagonized by chlordiazepoxide, phenobarbital, valproate, trimethadione and muscimol, but not by ethosuximide. This profile of action is similar to that of bicuculline, suggesting that lidocaine may bind to the GABA recognition site and to another site in the GABA-ionophore receptor complex. Phenytoin-induced excitation was antagonized by chlordiazepoxide, less effectively by phenobarbital or trimethadione, only minimally by valproate, and not by trimethadione or muscimol. Phenytoin is known to bind to picrotoxin and benzodiazepine receptor sites; these findings suggest that it may be excitatory at one or both of these sites.

Animals↗
PubMed2004

Opposite effects of depressant and convulsant barbiturate stereoisomers on acetylcholine release from the rat hippocampus in vivo.

BACKGROUND: It has been shown that the R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) induces loss of the righting reflex (LRR), while S(+)-MPPB causes pure excitatory effects, including convulsions, in vivo. METHODS: We studied the effects of the depressant and convulsant MPPB stereoisomers on rat hippocampal acetylcholine (ACh) release in vivo, using a brain microdialysis technique in freely moving animals. RESULTS: R(-)-MPPB 60 and 90 mg x kg(-1) i.p. decreased ACh release from the rat hippocampus by 44.1 (8.2)% and 60.8 (8.2)%, respectively. In the hippocampus, the local application of bicuculline, a gamma-aminobutyric acid (GABA)(A) receptor antagonist, 1 micromol litre(-1) antagonized the inhibitory effects of R(-)-MPPB 90 mg x kg(-1) i.p. In contrast, R(-)-MPPB, S(+)-MPPB 60 and 90 mg x kg(-1) i.p. increased ACh release to 151.8 (6.8)% and 169.6 (11.1)% of the basal release, respectively. CONCLUSIONS: Our results demonstrated that R(-)-MPPB decreased, while S(+)-MPPB increased, rat hippocampal ACh release and that the inhibitory effects of R(-)-MPPB may involve the GABA(A) receptor in vivo. These data imply that changes in hippocampal ACh due to these agents may be related to their central inhibitory and stimulatory actions in vivo.

Acetylcholine↗
PubMed1996

Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis.

We examined the anesthetic and convulsant properties of 16 unfluorinated to completely fluorinated aromatic compounds, having six to nine carbon atoms (e.g., benzene to 1,3,5-tris(trifluoromethyl)benzene), and four cycloalkanes (cyclopentane to cyclooctane). Benzene, fluorobenzene, toluene, p-xylene, ethylbenzene, and cyclopentane caused excitation (twitching, jerking, and hyperactivity), and three aromatic compounds (perfluorotoluene, p-difluorotoluene and 1,3,5-tris(trifluoromethyl)benzene) and three cycloalkanes (cyclohexane, cycloheptane, and cyclooctane) produced convulsions. Cyclooctane and 1,3,5-tris(trifluoromethyl)benzene were nonanesthetics. Except for nonanesthetics and perfluorotoluene (too toxic to test for anesthetic potency), all compounds produced anesthesia or decreased the minimum alveolar anesthetic concentration of desflurane. Aromatic compounds were more potent and lipid-soluble than n-alkanes (data from previous report) and cycloalkanes. All three series increasingly disobeyed the Meyer-Overton hypothesis as molecular size increased. For a particular number of carbons (e.g., cyclohexane, n-hexane, and benzene), the deviation was cycloalkanes > or = normal alkanes > aromatic compounds. These results suggest that molecular shape (including "bulkiness") and size provide limited clues to the structure of the anesthetic site of action.

Anesthesia, Inhalation↗
PubMed1999

Comparison of the effects of convulsant and depressant barbiturate stereoisomers on AMPA-type glutamate receptors.

BACKGROUND: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. METHOD: The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. RESULTS: Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. CONCLUSIONS: Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

Animals↗
PubMed1993

GABA-responses of CA3 neurones at epileptogenic threshold concentrations of convulsants.

Epileptogenic actions of convulsants are often attributed to weakened inhibitory synaptic mechanisms. This assumption was tested by studying GABA-induced postsynaptic membrane potential (MP) changes of CA3 neurones (guinea-pig) before and during exposure to bicuculline methoiodide (BMI), pentylenetetrazol (PTZ), penicillin (PEN) and caffeine (CAF). Under control conditions GABA ejections elicited polyphasic MP fluctuations (components I-III). After adding BMI, PTZ, PEN or CAF, early hyperpolarizations (component I) did not change at epileptogenic threshold concentrations. These convulsants, however, exerted differential effects on the depolarizing component II, but only threshold concentrations of penicillin strongly reduced the amplitude of this component. Simultaneously, component III was slightly accentuated. These findings indicate that changes of GABA responses are not an essential prerequisite for the generation of paroxysmal depolarizations.

Action Potentials↗