Provocation of Cerebral Seizures by Derangement of the Natural Balance Between Glutamic Acid and Γ‐aminobutyric Acid

Wiechert, P; Herbst, Anne

doi:10.1111/j.1471-4159.1966.tb03332.x

Cited by 48 publications

(12 citation statements)

References 28 publications

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“…In the present study, administration of pyridoxine from gestation on resulted in continual exposure to potentially toxic levels, and development of treated ER animals is subsequently impaired. The decrease in the excitatory/inhibitory amino acid ratio in these pyridoxine-treated ER mice may demonstrate that normal neurologic development and function is adversely affected by a shift in the neurotransmitter amino acid level toward a net inhibitory state (Wiechart and Herbst, 1966).…”

Section: Discussionmentioning

confidence: 97%

Effect of Sustained Pyridoxine Treatment on Seizure Susceptibility and Regional Brain Amino Acid Levels in Genetically Epilepsy‐Prone BALB/c Mice

et al. 1993

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Epilepsy-prone and epilepsy-resistant substrains were selectively bred from a strain of BALB/c mice; audiogenic-sensitive epilepsy-prone animals showed enhanced sensitivity to chemical convulsants. Treatment with pyridoxine (100 mg/L in drinking water) initiated at mating and continued throughout pregnancy and the life of the offspring abolished the enhanced sensitivity to chemical convulsants and reduced the severity of audiogenic seizures. Withdrawal of pyridoxine restored the enhanced seizure sensitivity. [1H] Nuclear magnetic resonance (NMR) spectroscopy of perchloric acid extracts of tissue was used to determine the concentrations of several compounds [N-acetylaspartate (NAA), GABA, glutamate, aspartate, alanine, taurine, creatine, cholines, inositol] in the hippocampus, neocortex, brainstem, and cerebellum of untreated and pyridoxine-treated 6-week-old female animals. The ratios of the concentrations of excitatory to inhibitory putative neurotransmitter amino acids tended to be higher in epilepsy-prone animals, with the most pronounced difference being a significantly elevated glutamate/GABA ratio in every brain region examined. Pyridoxine treatment abolished this imbalance in the hippocampus, brainstem, and cerebellum, but not in the neocortex. Treatment of epilepsy-resistant animals with pyridoxine using the same protocol decreased the glutamate/GABA concentration ratio in the hippocampus, brainstem, and neocortex and resulted in impaired development of the animals. The amino acid imbalance and the accompanying seizure susceptibility in these genetically epilepsy prone mice may originate from an inborn error in pyridoxine metabolism or in a pyridoxine-dependent enzyme system.

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Section: Discussionmentioning

confidence: 97%

Effect of Sustained Pyridoxine Treatment on Seizure Susceptibility and Regional Brain Amino Acid Levels in Genetically Epilepsy‐Prone BALB/c Mice

et al. 1993

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“…Clearly, additional studies exploring the cerebellum as a site of action of antiepileptic drugs are indicated. Finally, gammaamino-butyric acid (GABA) is thought to be the inhibitory transmitter released by P-cells (Roberts and Kuriyama 1968 ;Obata and Takeda 1969), and since a reciprocal relationship exists between whole brain GABA and seizure susceptibility (Kopeloff and Chusid 1965 ;Wiechert and Herbst 1966 ;Wood et al 1969) possible mediation of GABA in the antiepileptic action of DPH should also be explored.…”

Section: Discussionmentioning

confidence: 99%

Effects of Diphenylhydantoin and Other Antiepileptic Drugs on Epileptiform Activity and Purkinje Cell Discharge Rates

Julien

Halpern

1972

Epilepsia

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SUMMARY The effects of antiepileptic drugs on cerebellar Purkinje cell discharge rates and cerebral cortical epileptiform activity were studied in cats with penicillin foci in sensory‐motor cortex. In control experiments, extracellular microelectrode recordings of P‐cell activity revealed characteristic low‐frequency discharge rates during periods of cortical quiescence and discharge rates of 150 Hz occurring concomitant with focal cortical spike activity. P‐cell discharges abruptly ceased during development of cortical epileptiform bursts (CEB) which became generalized and maximal in both cerebral hemispheres. Following DPH (10 mg/kg i.v.) CEB frequency and duration were markedly reduced and sustained P‐cell discharge rates of 140 Hz were recorded. Following cerebellectomy in DPH‐treated animals, CEB activity intensified, was more frequent, involved both cerebral hemispheres, and was of much longer duration. Administration of DPH subsequent to cerebellectomy was less effective in reducing CEB activity. After phenobarbital (20 and 40 mg/kg i.v.) reduction of CEB activity was observed as was a consistent increase in P‐cell discharge frequency. Trimethadione (300 mg/kg i.v.) and acetazolamide (35 mg/kg i.v.) did not reduce CEB activity and no increase in P‐cell discharge rate was observed. Thus, after doses of antiepileptic drugs reducing CEB activity, cerebellar P‐cell discharge rates were increased. Conversely, P‐cell discharge rates did not increase following administration of antiepileptic drugs which did not decrease CEB activity. RÉSUMÉ Chez des chats porteurs de foyers de pénicilline dans le cortex sensorimoteur, on a étudié l'effet des drogues antiépileptiques sur la fréquence des décharges des cèllules de Purkinje dans le cervelet. Dans des conditions de contrôle, les enregistrements des cellules de Purkinje avec microélectrodes extracellulaires mettent en évidence des décharges caractéristiques de basse fréquence pendant les périodes de repos cortical et des décharges dont la fréquence est de 150 Hz en même temps que les décharges de pointes focales dans le cortex. Les décharges dans les cellules de Purkinje disparaissaient brutalement lors de l'apparition des bouffées épileptiques corticales (BEC) qui se généralisaient en augmentant d'amplitude sur les deux hémisphères. Après diphénylhydantoïne (DPH) (10 mg/kg, i.v.), la fréquence et la durée des BEC étaient nettement réduites et l'on enregistrait des décharges prolongées à 140 Hz dans les cellules de Purkinje. Après ablation du cervelet, chez les animaux traités par DPH, les BEC augmentaient en nombre, fréquence et durée et intéressaient les deux hémisphères. L'effet inhibiteur de la DPH sur les BEC était nettement moins évident après ablation du cervelet. Après phénobarbital (20 à 40 mg/kg i.v.), on observait une diminution des BEC ainsi qu'une diminution significative de la fréquence des décharges dans les cellules de Purkinje. La triméthadione (300 mg/kg i.v.) et l'acetazolamide (35 mg/kg i.v.) ne réduisaient pas les BEC et l'on n'observait pas d'aug...

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“…They measured the concentration of amino acids, and the activity of several enzymes including GAD, before and during convulsions and concluded that an inhibition of GAD (Wiechert and Gollnitz, 1968), or an alteration of the physiological balance between GABA and glutamic acid (Wiechert and Herbst, 1966;Wiechert and Gollnitz, 1969b;, or disturbances in ammonia metabolism (Wiechert and Gollnitz, 1969a) may be involved in the production of seizures. In unpublished studies on the effect of the intracisternal injection of PLP in mice, we have found that the administration of 0.5 Jlmol of PLP produces fatal tonic convulsions in 100% of the animals in 1-2 min.…”

Section: Intracranial and Topical Applicationmentioning

confidence: 98%

“…This action of PLP could be related to its convulsant effect observed when it is administered intracranially (Wiechert and Herbst, 1966;GOllnitz, 1968, 1969a), but, as discussed in Section 2, there are other alternatives for explaining the convulsant action of PLP. (Mechanism 3, Fig.…”

mentioning

confidence: 96%

Biochemical Pharmacology of GABA in CNS

Tapia

1975

Amino Acid Neurotransmitters

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Provocation of Cerebral Seizures by Derangement of the Natural Balance Between Glutamic Acid and Γ‐aminobutyric Acid

Cited by 48 publications

References 28 publications

Effect of Sustained Pyridoxine Treatment on Seizure Susceptibility and Regional Brain Amino Acid Levels in Genetically Epilepsy‐Prone BALB/c Mice

Effect of Sustained Pyridoxine Treatment on Seizure Susceptibility and Regional Brain Amino Acid Levels in Genetically Epilepsy‐Prone BALB/c Mice

Effects of Diphenylhydantoin and Other Antiepileptic Drugs on Epileptiform Activity and Purkinje Cell Discharge Rates

Biochemical Pharmacology of GABA in CNS

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