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Homocysteine induced convulsions: enhancement by vitamin B6 and inhibition by hydrazine.

The effects of pyridoxal phosphate, pyridoxine and hydrazine were studied on homocysteine-induced seizures in mice. Both of the B6 vitamers significantly decreased the latency and increased the severity, lethality and duration of seizures induced by homocysteine. The B6 inhibitor hydrazine sulfate, which is normally a convulsant, prevented the tonic component of the convulsions and increased the latency to the clonic component. This experiment indicates that a vitamin B6 dependent step is critically involved in the metabolic changes which precede homocysteine seizures.

Animals↗

Membrane depolarization and prolongation of calcium-dependent action potentials of mouse neurons in cell culture by two convulsants: bicuculline and penicillin.

The convulsant compounds bicuculline (BICUC) and penicillin (PCN) are antagonists of GABA-mediated synaptic inhibition. In addition, we have shown that BICUC and PCN produced membrane depolarization of mouse spinal cord neurons in primary dissociated cell culture by blocking a potassium conductance, a non-synaptic direct effect. Both compounds also prolonged calcium-dependent action potentials of mouse dorsal root ganglion and spinal cord neurons in cell culture. Thus, BICUC and PCN had both synaptic and non-synaptic actions. The possibility that both synaptic and non-synaptic actions of BICUC and PCN are involved in their convulsant mechanism of action is discussed.

Action Potentials↗

Contrasting effects of a convulsant (CHEB) and an anticonvulsant barbiturate (phenobarbitone) on amino acid release from rat brain slices.

The effects of a convulsant barbiturate, 5(2-cyclohexylidine-ethyl)-5-ethyl barbituric acid (CHEB), and phenobarbitone (PhB) on the release of exogenous D-aspartate and GABA from slices of rat cerebral cortex were investigated. While PhB inhibited potassium-evoked release of D-aspartate more so than that of GABA, CHEB potently inhibited potassium-evoked GABA release and stimulated evoked D-aspartate release, in a concentration-dependent manner. These actions are consistent with the observed in vivo convulsant and anticonvulsant properties of these barbiturates. CHEB, but not PhB also elevated spontaneous efflux of both amino acids. The actions of these barbiturates were further studied in calcium- and sodium-free media, and in the presence of tetrodotoxin and ruthenium red, agents known to alter ion flux across neuronal membranes. The results obtained indicate that different ionic mechanisms may be involved in the release of excitatory and inhibitory amino acid transmitters.

Animals↗

Reversible suppression of amygdaloid kindled convulsion following unilateral gabaculine injection into the substantia innominata.

Amygdaloid kindled generalized convulsion was reversibly blocked despite continued afterdischarge generation by amygdaloid stimulation for about 60 h following intracerebral administration of gabaculine, a GABA-transaminase inhibitor, into the substantia innominata (SI) ipsilateral to the side of amygdaloid kindling. It is suggested that the SI plays an important role in convulsive seizure generalization of amygdaloid origin.

Action Potentials↗

Decreased levels of brain cyclo-oxygenase products as a possible cause of increased seizure susceptibility in convulsion-prone gerbils.

Basal levels of 5 cerebral prostanoids (PGD2, PGF2 alpha, PGE2, 6-keto-PGF1 alpha and thromboxane/TX/B2) were measured radioimmunologically in normal and convulsion-prone gerbils. Significantly less PGD2,PGE2 and 6-keto-PGF1 alpha was found in the brain of seizure-sensitive animals. After treatment with indomethacin, which reduced the amount of brain cyclo-oxygenase products, also normal gerbils exhibited convulsions following environmental stress. The results are in accordance with the hypothesis that endogenous prostanoids play a role in the regulation of seizure susceptibility.

Alprostadil↗

Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals.

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminals by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromuscular preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anticonvulsant actions.

4-Aminopyridine↗

The formation and regional distribution of prostaglandins D2 and F2 alpha in the brain of spontaneously convulsing gerbils.

The distribution of the two major cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha) in 7 different regions of the brain (medulla, cerebellum, hypothalamus, striatum, midbrain, hippocampus and cerebral cortex) was studied. Basal levels were highest in hypothalamus and cortex. Following convulsions elicited by environmental stress prostaglandin concentrations increased in all areas, with largest increases (10-20-fold) in hippocampus and cortex, reaching 70 ng/g PGD2 in hippocampus and 115 ng/g PGD2 in cortex. These results demonstrate that, during spontaneous seizures, there is a greater increase in prostanoid production in those areas involved in the convulsive process.

Animals↗

Disruption of behavioral recovery by the anti-convulsant phenobarbital.

The effects of the anti-convulsant phenobarbital on recovery of function was assessed. Phenobarbital, which is frequently administered to humans after brain injury, was injected for 7 days beginning 48 h after unilateral cortex lesions in rats. Recovery from somatosensory deficits was significantly delayed in phenobarbital treated animals. These results provide additional evidence that anti-convulsants interfere with recovery when administered after brain damage.

Animals↗

Distribution of Fos-positive neurons in cortical and subcortical structures after picrotoxin-induced convulsions varies with seizure type.

The distribution of Fos protein was mapped in rat brain following a single non-focal convulsive seizure. Single seizures were induced with intravenous picrotoxin in unhandled animals housed in isolation. Different convulsive behaviours occurred unpredictably. The least severe seizures were predominantly localised to the face, head and forelimbs, without loss of posture control (restricted seizures). The most extensive seizures affected all limbs and trunk, sometimes with falling (generalised seizures). There was a correlation between seizure behaviour and distribution of Fos induction. After restricted seizures, Fos was induced at highest levels in neocortex and piriform cortex and was prominent in entorhinal cortex, caudal-ventral caudate-putamen and amygdala. Regions of thalamus were consistently and lightly labelled, but Fos induction did not occur in hippocampus. After generalised seizures, there was Fos induction in cortex but less than after restricted seizures and, in three of four animals, also in dentate gyrus, hippocampus and subiculum. There was occasional or variable labelling of thalamus, basolateral amygdala and caudate-putamen. One animal with generalised seizures showed no hippocampal Fos induction. The findings indicate that picrotoxin induces seizures with at least two different patterns of neuronal involvement. The cortex, part of the caudate-putamen, amygdala and thalamus are involved in restricted seizures while the hippocampus, cortex and thalamus are involved in generalised seizures. The results do not support the view that generalised seizures are a progression from restricted forms. Cortical Fos involvement is entirely consistent with the participation of cortex in non-focal epilepsy. In these non-focal seizures, the dentate-hippocampus may be a source of excitation to cortex in the generalised group while the cortex appears to be the predominant site of excitation in the restricted group.

Animals↗

Intrastriatal methylmalonic acid administration induces rotational behavior and convulsions through glutamatergic mechanisms.

The effect of intrastriatal administration of methylmalonic acid (MMA), a metabolite that accumulates in methylmalonic aciduria, on behavior of adult male Wistar rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of MMA (buffered to pH 7.4 with NaOH) or NaCl. MMA induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior and convulsions were prevented by intrastriatal preadministration of MK-801 and attenuated by preadministration of succinate. This study provides evidence for a participation of NMDA receptors in the MMA-induced behavioral alterations, where succinate dehydrogenase inhibition seems to have a pivotal role.

Animals↗

Gonadal hormones and picrotoxin-induced convulsions in male and female rats.

The sensitivity to the GABA-blocking agent picrotoxin was studied in young and adult male and female rats, in rats treated with gonadal hormones and in gonadectomized male and female rats. Picrotoxin was equipotent in producing convulsions in male and female 20-day-old rats. Adult females tended to be more, while adult males were considerably less sensitive to picrotoxin than young rats. Picrotoxin was equipotent in displacing t-[3H]butylbicycloorthobenzoate ([3H]TBOB) binding to crude cortical and cerebellar membranes from male and female rat brain. Chronic treatment of male rats, beginning with 30 days of age, with estradiol benzoate enhanced their sensitivity to picrotoxin, while an analogous treatment of female rats with testosterone propionate was ineffective. Thirty days following castration adult male rats had shorter latencies to the appearance of picrotoxin-induced convulsions and a higher incidence of death. Ovariectomy in females failed to modify the sensitivity to picrotoxin. The results suggest that gonadal hormones have a crucial role in the development of sex related differences in the response of rats to picrotoxin and presumably to other GABA-related drugs. When developed, the male type of reactivity appears to depend more, and the female type less on the presence of circulating hormones in the blood.

Analysis of Variance↗

Paroxysmal spike and wave activity in drowsiness in young children: its relationship to febrile convulsions.

Paroxysmal rhythmic theta waves appearing during early stages of sleep have long been recognized in the EEGs of normal children. A similar pattern with intermixed spikes appears to have a different correlation. We called this pattern 'hypnagogic paroxysmal spike wave activity' or 'hypnagogic PSW.' This investigation was designed to test whether there exists a relationship between hypnagogic PSW, febrile convulsions (FC) and age. We selected 3 cohorts of children: G-1 or normal control consisted of 94 children selected with the following criteria: complete normal neurodevelopmental examination and no personal or family history of FC, epilepsy, or other neurological disorder. They all had one EEG obtained without drug induction showing a clear sequence of awake-drowsy-sleep-arousal-awake states. G-2 or pathological control group consisted of 126 children selected at random, referred to the Division of Neurophysiology at the Children's Hospital Medical Center for any problem excluding FC. At least one EEG met the criteria mentioned above. G-3 or FC group consisted of 375 children in whom the very first seizure was associated with fever without evidence of other causes for the convulsion. All met the same EEG criteria of G-1 and G-2. The medical record of 169 children of this group (40 with hypnagogic PSW and 129 without hypnagogic PSW) were reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗

Tolerance to cocaine-induced convulsions in the cat.

Two groups of female cats (6 each) were used: (1) a seizure group which received a minimum convulsive dose (MCD) of cocaine i.v., and (2) a subseizure group which received a subconvulsive dose of cocaine i.v., for 13 successive days. Determination of the MCD across 13 days in the seizure group and on Day 14 in the subseizure group revealed significant tolerance to cocaine-induced convulsions. However, reverse tolerance to cocaine-induced abnormal behavior developed as dystonic posture and speed of stereotyped movement increased during the 13-day treatment period in the subseizure group. These data are discussed in terms of local anesthetic and catecholaminergic effects of cocaine, as well as possible differential effects of various routes of administration.

Animals↗

Methyl-beta-carboline-induced convulsions are antagonized by Ro 15-1788 and by propyl-beta-carboline.

Injected i.v. into baboons, Ro 15-1788 (a benzodiazepine antagonist) and propyl-beta-carboline-3-carboxylate did not modify either the behavior or the electroencephalogram at doses up to 2 mg/kg. Methyl-beta-carboline-3-carboxylate is a potent convulsant at doses of 20 micrograms/kg in photosensitive baboons and 100 micrograms/kg in non-photosensitive baboons. These convulsive doses of methyl-beta-carboline-3-carboxylate are effectively antagonized by 0.5 mg/kg of Ro 15-1788 and also by 2 mg/kg of propyl-beta-carboline-3-carboxylate.

Animals↗

The benzodiazepine antagonist, Ro 15-1788 does not decrease ethanol withdrawal convulsions in rats.

The effects of the benzodiazepine antagonist, Ro 15-1788 on ethanol withdrawal convulsions were investigated in rats. The study originated from recent reports of benzodiazepine binding activity in urine of alcoholics during withdrawal. No alleviation of convulsions was found with Ro 15-1788. This suggested that this component of the withdrawal syndrome is not due to endogenous production of a benzodiazepine inverse agonist (contragonist), as Ro 15-1788 prevents the action of this type of compound.

Animals↗

Isoniazid-induced convulsions in rats: effects of Ro 15-1788 and beta-CCE.

Dose-response curves for the convulsant effect of isoniazid were determined in male rats. The specific benzodiazepine antagonist Ro 15-1788, at doses from 20 to 100 mg/kg i.v. or at 300 mg/kg p.o., failed to produce any relevant shift of the isoniazid dose-response curves to the left (proconvulsant) or to the right (anticonvulsant). In contrast, the benzodiazepine receptor ligand ethyl-beta-carboline-3-carboxylate (beta-CCE) 10 mg/kg i.v. produced a clear-cut shift to the left of the isoniazid dose-response curve. Ro 15-1788 was inactive up to high p.o. or i.v. doses, versus convulsions induced by a low supraliminal dose of isoniazid, whereas beta-CCE had a significant proconvulsant effect beginning at 5 mg/kg i.v. This effect of beta-CCE was dose dependently antagonized by Ro 15-1788. In conclusion, in the present experimental conditions Ro 15-1788 showed no inverse agonistic properties at benzodiazepine receptors, in contrast to beta-CCE.

Animals↗

Inhibition of aminophylline-induced convulsions in mice by antiepileptic drugs and other agents.

Common antiepileptic drugs and agents affecting different neurotransmitter systems were studied against aminophylline (280 mg/kg i.p.)-induced convulsions in mice. All drugs and agents were administered i.p. Diazepam and phenobarbital antagonized the whole seizure pattern and the respective ED50 values for the clonic phase were 3.5 and 62 mg/kg. Valproate at 500 mg/kg protected fewer than 50% of mice against the clonic phase. The remaining antiepileptics (acetazolamide, up to 1,000 mg/kg; carbamazepine and diphenylhydantoin, up to 50 mg/kg; ethosuximide, 500 mg/kg and trimethadione, 400 mg/kg) were totally ineffective in this respect. Propranolol (up to 20 mg/kg), baclofen (20 mg/kg), gamma-hydroxybutyric acid (300 mg/kg), aminooxyacetic acid (20 mg/kg), clonidine (up to 0.2 mg/kg), ketamine (30 mg/kg), atropine (20 mg/kg), papaverine (50 mg/kg) and L-phenylisopropyladenosine (2 mg/kg) did not affect the clonic phase either. Only antagonists of N-methyl-D-aspartic acid excitation, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid afforded protection against aminophylline-induced clonic seizure activity. The results show that aminophylline convulsions are relatively resistant to antiepileptic drugs and suggest that antagonists of excitatory transmission are potential antiaminophylline drugs.

2-Amino-5-phosphonovalerate↗

Ethacrynic acid-induced convulsions and brain noradrenaline in mice.

The intracerebroventricular injection of ethacrynic acid (a 50% convulsive dose; 50 micrograms/mouse) accelerated brain noradrenaline turnover and decreased noradrenaline contents. The decrease in noradrenaline contents was antagonized by 2-amino-5-phosphonovalerate but not by diazepam. Both 2-amino-5-phosphonovalerate and diazepam suppressed the incidence of ethacrynic acid-induced convulsions while reserpine, alpha-methyl-para-tyrosine or FLA-63 augmented it. The results suggest that stimulation by ethacrynic acid of excitatory amino acid neurons enhances-noradrenergic neuronal anticonvulsive activity.

Animals↗