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PubMed2000

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels.

A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2, 2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3, 3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist-activated chloride currents in human GABA(A), glycine, and GABA(C) rho(1) receptors expressed in HEK 293 cells. GABA(A) and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA(A) alpha(2)beta(1) and alpha(2)beta(1)gamma(2s) receptors, but had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on GABA responses at GABA(C) rho(1) receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA(A) and glycine receptors, but had no effect on GABA responses at GABA(C) rho(1) receptors. Point mutations in GABA(A) and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA(A) receptor had only modest effects on the inhibitory actions of flurothyl. GABA(A) receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA(A) receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA(A) and/or glycine receptors.

Amino Acid Sequence↗
PubMed1997

Role of nitric oxide in the convulsive seizures induced by fluoroquinolones coadministered with 4-biphenyl acetic acid.

1. Contribution of nitric oxide to the convulsive seizures induced by fluoroquinolones (FQs) coadministered with 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen, was assessed in mice. 2. Enoxacin + 4-biphenyl acetic acid caused clonic seizures in all treated mice, followed by tonic seizures and death. These events were associated with a significant increase in intracerebellar cyclic GMP. 3. Pretreatment with the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methylester (L-NAME), but not with D-NAME, significantly reduced the incidence of convulsions and lethality, as well as the increase in cyclic GMP. 4. Pretreatment with N-methyl-D-aspartic acid (NMDA)-receptor antagonist, MK-801, inhibited only the transition of clonic seizure to tonic seizure without affecting the incidence of clonic seizure and lethality. 5. These findings suggest that FQs + BPAA exert convulsions by activating NOS partly through the mediation of the NMDA receptor in the brain cells.

Animals↗
PubMed1999

The molecular structure of 2alpha-hydroxyneoanisatin and structure-activity relationships among convulsant sesquiterpenes of the seco-prezizaane and picrotoxane types.

The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural types with respect to the mode of cyclisation, did not induce anisatin/picrotoxinin-like convulsions in mice. Based on these results and literature data for other seco-prezizaanes, structural requirements for convulsant activity are discussed. Comparison of the three dimensional molecular shape and electrostatic properties of active and inactive seco-prezizaane type lactones with compounds of the picrotoxane type resulted in the identification of a common pharmacophore structure for these different skeletal classes of convulsant natural products.

Animals↗
PubMed2000

Ligand binding to CNS muscarinic receptor is transiently modified by convulsant 3-mercaptopropionic acid administration.

The administration of convulsant drugs has proven a powerful tool to study experimental epilepsy. We have already reported that the administration of convulsant 3-mercaptopropionic acid (mp) at 150 mg/kg enhances binding affinity of muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) to certain rat CNS membranes during seizure and postseizure without affecting site number. Results obtained with a 100-mg/kg dose of mp have shown reversible increases in [3H]QNB binding to cerebellum and hippocampus, whereas a delayed response has been found in striatum. Neither a subconvulsant dose nor in vitro addition modifies binding. In order to evaluate preseizure, seizure as well as early (30 min) and late (24 h) postseizure stages, we employed a 50 mg/kg dose and tested [3H]QNB binding to CNS membranes. Changes in binding were as follows (in %): in cerebellum, +37, +86, and +40 at preseizure, seizure and early postseizure stages, respectively, but there was a decrease at late postseizure; in hippocampus, +27 at pre- and seizure stages, but a decrease at early and late postseizure. No changes were found in striatum or cerebral cortex membranes at any stage studied. Saturation curves analysed by Scatchard plots indicated that changes in [3H]QNB binding to cerebellar membranes are attributable to an increase in ligand affinity at seizure, followed by a decrease in binding site number at postseizure. A similar profile was observed for hippocampus except that the decrease in binding site number, though lower than at postseizure, was already evident at seizure stage. Results confirm a region-specific response to the convulsant and transient changes provide an example of neuronal plasticity.

3-Mercaptopropionic Acid↗
PubMed1998

CNS adenosine A1 receptors are altered after the administration of convulsant 3-mercaptopropionic acid and cyclopentyladenosine: an autoradiographic study.

Rat CNS adenosine A1 receptors were studied by quantitative autoradiography after the administration of convulsant 3-mercaptopropionic acid (MP) and an adenosine analogue cyclopentyladenosine (CPA), using 2-chloro-N6-[cyclopentyl-2,3,4,5-3H adenosine]-([3H]CCPA) as radioactive ligand. Specific binding was quantified in hippocampus, cerebellum, cerebral cortex, thalamic nuclei, superior colliculus and striatum, and the highest densities were found in CA1, CA2, and CA3 hippocampus subareas and the lowest levels in superior colliculus and striatum. MP administration (150 mg/kg, i.p.) produced significant increases in [3H]CCPA binding in CA1 subarea at seizure (15%) and postseizure (21%) and in CA2 at seizure (15%) but a tendency to decrease in dentate gyrus. There was an increase in cerebellum at seizure (18%) but no significant changes in the other studied regions. CPA injection (2 mg/kg, i.p.) enhanced [3H]CCPA binding in CA1 and CA2 areas (17-18%) but not in CA3 area of the hippocampus. When CPA was administered before MP, which delayed seizure onset, an increase in [3H]CCPA binding in CA1 hippocampus subarea (19%) and cerebellum (28%) was also observed. Results showed that the administration of convulsant MP and adenosine analogue CPA exerts differential effects on adenosine A1 receptors in CNS areas; hippocampus is the most affected area with all treatments, specially CA1 subarea, supporting an essential role in convulsant activity as well as in seizure prevention.

3-Mercaptopropionic Acid↗
PubMed2001

Induction of brain-derived neurotrophic factor by convulsant drugs in the rat brain: involvement of region-specific voltage-dependent calcium channels.

A high level of hippocampal brain-derived neurotrophic factor (BDNF) in normally aged as compared with young rats suggests that it is important to maintain a considerable level of hippocampal BDNF during aging in order to keep normal hippocampal functions. To elucidate possible mechanisms of endogenous BDNF increase, changes in levels of BDNF were studied in the rat brain following systemic administration of various convulsant agents; excitotoxic glutamate agonists, NMDA, kainic acid and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA); GABA receptor antagonists, picrotoxin, pentylenetetrazole (PTZ) and lindane (gamma-hexachlorocyclohexane); and L-type voltage-dependent calcium channel agonist, BAY-K 8644. Kainic acid and AMPA, but not NMDA, caused remarkable increases in BDNF protein in the rat hippocampus and entorhinal cortex. Picrotoxin, PTZ and lindane stimulated BDNF production in the entorhinal cortex and also in the hippocampus of rats showing very severe convulsions. On the other hand, BAY-K 8644 treatment increased BDNF levels in the neocortex and entorhinal cortex. Maximal levels of BDNF protein were observed at 12--24 h, 8--16 h and 6 h following administration of kainic acid, PTZ and BAY-K 8644, respectively. Kainic acid stimulated BDNF synthesis in presynaptic hippocampal granule neurons, but not in postsynaptic neurons with its receptors, while PTZ and BAY-K 8644 produced the same effects in postsynaptic neurons in the entorhinal cortex (in granule neurons in the hippocampus) and in the whole cortex, respectively. Nifedipine inhibited almost completely BAY-K 8644, but not PTZ, effects. omega-Conotoxin GVIA and DCG-IV partially blocked kainic acid-induced enhancement of BDNF, indicating involvement of L-type and N-type voltage-dependent calcium channels, respectively. In addition, BDNF levels in the hippocampus of mice deficient in D-myo-inositol-1,4,5-triphosphate receptor gene were scarcely different from those in the same region of controls, suggesting little involvement of intracellular calcium increase through this receptor. BAY-K 8644, but not kainic acid or PTZ, stimulated the phosphorylation of cyclic AMP responsive element binding protein. Our results indicate convulsant-dependent stimulation of BDNF production and involvement of region-specific voltage-dependent calcium channels.

Animals↗
PubMed1963

CONVULSIVE SYNDROME IN RABBITS INJECTED WITH FAT EMULSION AND HEPARIN.

Functionally hepatectomized rabbits showed convulsions and coma within 2 hours after the intravenous injection of fat emulsion and heparin. Intravenous injection of the detergent triton prevented this syndrome, if given before the fat emulsion and heparin, and reversed it if given subsequently. Extremely high plasma non-esterified fatty acid levels were noted in rabbits showing the convulsive syndrome, but not in animals that received the detergent. The mechanism of the convulsions probably includes the toxicity of high amounts of non-esterified fatty acids.

Animals↗
PubMed1997

Enhanced choline acetyltransferase activity does not explain the action of inhaled convulsants.

Enhancement of choline acetyltransferase (ChAT) activity and increased intraneuronal acetylcholine (ACh) may explain the convulsant activity of some inhaled compounds. Enflurane, for example, enhances such activity. Accordingly, we measured choline acetyltransferase (ChAT) activity in rat cortical synaptosomes in the presence of two inhaled convulsants, flurothyl (CF3CH2OCH2CF3) and 1,2-dichlorohexafluorocyclobutane at partial pressures below and greatly exceeding those which produce convulsions in vivo. Neither agent changed the kinetic parameters, maximum velocity (vmax) or Michaelis constant (Km). The vmax for controls in the flurothyl series was 016 (0.06) nmol mg-1 min-1 and the Km was 0.23 (0.11) mmol litre-1. For the 1,2-dichlorohexafluorocyclobutane series of experiments the results for the controls were vmax 0.23 (0.10) nmol mg-1 min-1 and Km 0.20 (0.08) mmol litre-1. Modification of ChAT activity did not contribute to the excitatory effects of these agents.

Administration, Inhalation↗
PubMed1963

Effects of asarone and beta-asarone on conditioned responses, fighting behaviour and convulsions.

In the Ayurvedic system of medicine, the roots and rhizomes of an indigenous Indian plant Acorus calamus are used together with the roots of Rauwolfia serpentina for treating many mental ailments. The influence of asarone and beta-asarone (the trans and cis forms of 2,4,5-trimethoxy-1-propenyl benzene), two active principles of Acorus calamus, when given alone and together with either reserpine or chlorpromazine, has been studied on the conditioned avoidance response of trained rats, on the fighting behaviour of paired mice subjected to mild foot shock and on electro-convulsions. Except for electro-convulsions, asarone in small doses potentiates the effects of reserpine and of chlorpromazine; beta-asarone has no such effect. Estimation of the 5-hydroxytryptamine content of rat brain showed that neither acorus oil nor its active principles increase the concentration of 5-hydroxytryptamine; nor do these compounds cause an additional decrease in the 5-hydroxytryptamine content of the brains of animals treated with reserpine. It is concluded that the potentiating effect of these principles is unrelated to 5-hydroxytryptamine concentration. In experiments using electro-convulsions, asarone increased the percentage mortality of animals treated with chlorpromazine but not of those treated with reserpine.

Acorus↗
PubMed1977

Effects of N-methylamino acids and convulsants on spontaneous action potentials in guinea-pig cerebellar slices.

1. N-methyl-gamma-aminobutyrate (N-methylGABA), N-methylglycine, N-methyltaurine and N-methylbeta-alanine diminished the frequency of spontaneous spike discharges in guinea-pig cerebellar slices. Usually a weak excitatory effect preceded the inhibition. 2. The inhibitory effects of N-methylGABA and N-methylbeta-alanine were competitively antagonized by both picrotoxin and strychnine. 3. The inhibitory action of N-methyltaurine was competitively suppressed by strychnine and by low concentrations of picrotoxin. 4. The inhibitory action of N-methylglycine was suppressed by strychnine but not by picrotoxin. The suppression was competitive at low concentrations of strychnine. 5. N-methylDL-glutamate brought about a strong inhibition followed by a strong excitation of the neurones. The inhibitory effects were competitively suppressed by both picrotoxin and strychnine. Neither convulsant affected the excitation. 6. Whereas L- or D-glutamate caused only excitation in the majority of cells examined, a small proportion of the cells exhibited inhibition preceding the excitation by L- or D-glutamate. Such inhibitory effects were suppressed by picrotoxin but not by strychnine. 7. Kinetic analyses of the dose-response curves for the N-methylamino acid in the presence or absence of the convulsant indicated that the number of molecules of the amino acid combining with the receptor site to produce a response was 3 for N-methylGABA, 2 for N-methylglycine, 3 for N-methyltaurine, 3 for N-methylbeta-alanine. The corresponding value was 1 for N-methylDL-glutamate (inhibition). The number of molecules of convulsant combining with the receptor site was calculated to be 2 for picrotoxin with N-methylGABA, N-methylbeta-alanine and N-methylDL-glutamate and 1 for strychnine with all N-methylamino acids examined.

Action Potentials↗
PubMed1983

Convulsant-induced depression of amino acid responses in cultured mouse spinal neurones studied under voltage clamp.

A two-microelectrode voltage-clamp technique was used to record membrane current responses induced by the application of the neutral amino acids, gamma-aminobutyric acid (GABA) and glycine, to mouse spinal neurones maintained in cell culture. Membrane current responses to GABA were depressed by the convulsant agents, bicuculline, picrotoxin and pentylenetetrazole. Membrane current responses to glycine were depressed by the convulsant compound, strychnine. Analysis of the fluctuations in membrane current about the mean response during prolonged applications of GABA revealed that neither the conductance nor the average open-time of GABA-activated ion-channels was altered in the presence of picrotoxin or bicuculline. Pentylenetetrazole caused a reduction in the open-time of GABA-activated ion-channels but this effect alone was too small to account for the depression of the current response. A similar analysis of glycine-induced responses in the presence of strychnine revealed that the depression of glycine responses by strychnine was not associated with any changes in the conductance or average open-time of glycine-activated ion-channels. We therefore conclude that the convulsant compounds act by reducing the rate of activation of ion-channels by the neutral amino acids either through a reduction in the number of free receptors or by a change in the kinetics of channel activation.

Amino Acids↗
PubMed1988

Convulsions and cerebral inositol-1-phosphate levels in rats treated with diisopropyl fluorophosphate.

In order to examine the relationship of organophosphate-induced cholinergic stimulation to phosphoinositide (PI) hydrolysis in the brain, diisopropyl fluorophosphate (DFP; 1.3 or 1.5 mg/kg subcutaneously) was given to rats pretreated with saline or LiCl (5 meq/kg subcutaneously). Behaviour was monitored 60 min. after the administration of DFP, and inositol-1-phosphate (IP1), an intermediate in PI metabolism, was measured in the brain DFP alone caused tremors, whereas with LiCl pretreatment, DFP caused tremors and tonic-clonic convulsions. DFP alone did not increase IP1 above control levels. LiCl alone elevated IP1 2-5 fold but did not alter rat behavior. With LiCl pretreatment, DFP caused IP1 to increase 2-4 fold above LiCl control values in convulsing rats. LiCl increased the potential of DFP to induce convulsions and greatly amplified IP1 elevations induced by DFP.

Animals↗
PubMed1991

Effects of anesthetics and convulsants on the resting potassium conductance in squid nerve.

The effects of some fluorinated anesthetics and convulsants on the ionic conductances of the axon membrane of the squid Loligo forbesi are described. The substances studied were the inhalation anesthetics enflurane (CF2HOCF2CClFH) and isoflurane (CF2HOCClHCF3) and the convulsants flurothyl (CF3CH2OCH2CF3) and trichlorofluormethane (CCl3F). At low concentrations (0.4-0.8 mM), none of these substances significantly affected the voltage-dependent Na and K channels of the nerve. However, at these concentrations each substance produced a depolarization of the resting potential and reduced the potassium conductance of the resting membrane. This was associated with a tendency to cause axonal hyperexcitability. The potassium conductance of the resting membrane was separated into a component arising from residual open Hodgkin-Huxley delayed rectifier K channels and another voltage-independent component (g'k). The former component was insensitive to the test substances at 0.4-0.8 mM, while g'k was inhibited by 40-80%. It is suggested that the convulsant activity of certain small fluorinated molecules, and the proconvulsant actions of certain clinical anesthetics at low concentrations, may be related to the inhibition of a resting, voltage-independent potassium conductance system in the nerve membrane.

Action Potentials↗
PubMed1963

CONVULSANT DRUG ACTION ON NEURONALLY ISOLATED CEREBRAL CORTEX.

After topical application of thiosemicarbazide, semicarbazide, or isoniazid to the surface of an isolated region of cortex, convulsive responses to electrical stimulation appeared only after a finite number of normal responses had been elicited, and disappeared again if stimulation was interrupted for about 10 minutes. With any of the other convulsant drugs tested, development of the convulsive pattern was independent of whether or not the cortex was stimulated. The two groups of drugs evidently have dijferent modes of action.

Cats↗
PubMed1982

Interaction of convulsive ligands with benzodiazepine receptors.

The gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, which is composed of distinct proteins embedded in the neuronal plasma membrane, is important for several effects of benzodiazepines, including protection afforded against convulsions. During structural modification of ethyl beta-carboline-3-carboxylate an agent was discovered which has high affinity for brain benzodiazepine receptors but which is a potent convulsant. Also in contrast to benzodiazepines, this type of benzodiazepine receptor ligand favors benzodiazepine receptors in the non-GABA-stimulated conformation, which may explain the convulsive properties.

Allosteric Regulation↗
PubMed1986

Effect of CGS-8216 on high-dose flurazepam convulsive threshold.

Flurazepam, a clinically proven and widely accepted sedative hypnotic, has been shown by a number of investigators to produce convulsions at toxic doses. In the present study, CGS-8216, a benzodiazepine receptor antagonist, reduced the dose of flurazepam required to produce convulsions. This suggests that the convulsant action of FLZ is exerted at a site other than the benzodiazepine receptor.

Animals↗
PubMed2002

Toxic cocaine- and convulsant-induced modification of forced swimming behaviors and their interaction with ethanol: comparison with immobilization stress.

BACKGROUND: Swimming behaviors in the forced swimming test have been reported to be depressed by stressors. Since toxic convulsion-inducing drugs related to dopamine [cocaine (COC)], benzodiazepine [methyl 6,7-dimethoxy-4-ethyl-beta-carboline-carboxylate (DMCM)], gamma-aminobutyric acid (GABA) [bicuculline (BIC)], and glutamate [N-methyl-D-aspartate (NMDA)] receptors can function as stressors, the present study compared their effects on the forced swimming behaviors with the effects of immobilization stress (IM) in rats. Their interactions with ethanol (EtOH), the most frequently coabused drug with COC which also induces convulsions as withdrawal symptoms but interferes with the convulsions caused by other drugs, were also investigated. RESULTS: Similar to the IM (10 min) group, depressed swimming behaviors (attenuated time until immobility and activity counts) were observed in the BIC (5 mg/kg IP) and DMCM (10 mg/kg IP) groups at the 5 h time point, after which no toxic behavioral symptoms were observed. However, they were normalized to the control levels at the 12 h point, with or without EtOH (1.5 g/kg IP). In the COC (60 mg/kg IP) and NMDA (200 mg/kg IP) groups, the depression occurred late (12 h point), and was normalized by the EtOH cotreatment. At the 5 h point, the COC treatment enhanced the swimming behaviors above the control level. CONCLUSIONS: Although the physiological stress (IM), BIC, and DMCM also depressed the swimming behaviors, a delayed occurrence and EtOH-induced recovery of depressed swimming were observed only in the COC and NMDA groups. This might be correlated with the previously-reported delayed responses of DA and NMDA neurons rather than direct effects of the drugs, which could be suppressed by EtOH. Furthermore, the characteristic psychostimulant effects of COC seemed to be correlated with an early enhancement of swimming behaviors.

Animals↗
PubMed2003

Effect of harmane on the convulsive threshold in epilepsy models in mice.

The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

Animals↗