Effects of acute and chronic phenytoin on the electrolyte content and the activities of Na+, K+-, Ca2+, Mg2+-, and HCO3- -ATPases and carbonic anhydrase of neonatal and adult rat cerebral cortex

Summary: Various parameters of anion and cation transport were measured in the cerebral cortex of neonatal (3-day-old) and adult rats following acute and chronic treatment with phenytoin (PHT). Acutely, PHT significantly inhibited the enzyme Na+, K+ -ATPase in both neonatal and adult rats. This effect was accompanied by a significant increase in cerebral cortical Na+ content and a decrease in K+ content only in neonatal animals. Chronic treatment (two and four times a day for 7 days) of adult rats with PHT significantly reduced Na+ content without affecting whole homogenate Na+, K+ -ATPase activity. The activity of this enzyme was markedly increased in the myelin- (glial product) and slightly decreased in the synaptosomal- (neuronal) fractions following chronic (four times a day for 7 days) PHT treatment. These results suggest that PHT differentially affects the two forms (neuronal and glial) of the enzyme Na+, K+-ATPase. The possible relevance of this hypothesis in relationship to the anticonvulsant and excitatory properties of PHT is discussed. Chronic (two and four times a day for 7 days) PHT treatment increased both DNA content and activity of the glial marker enzyme carbonic anhydrase. Activity of the mitochondrial enzyme HCO3--ATPase was also increased following chronic PHT treatment. These two enzymes are intimately involved in the regulation of HCO3--Cl- transport across glial cell and mitochondrial membranes, and these results suggest that PHT is able to affect beneficially glial regulatory processes. The ability to enhance glial regulation of anions and cations in extracellular fluid provides new and important insights into the mechanism of the anticonvulsant action of PHT. RESUME Differents parametres du trasportanionique et cationique ont ete mesures dans le cortex cerebral de rats nouveaux-nes (3 jours) et adultes apres traitement aigu et chronique par la PHT. En traitement aigu la PHT inhibait de fa¸on significtive l'enzyme Na+, K+-AtPase chez les rats adultes et nouveaux-nes. Cet effet s'accompagnait d'une augmentation significative du contenu cortical en sodium (Na+) chez les animaux nouveaux-nes seulement. En traitement chronique (2 fois/jour et 4 fois/jour pendant 7 jours) ches les rats adultes la PHT reduisait de fa¸on significative le Na+ sans affecter l'ensemble de l'activite Na+,K+-ATPase. L'activite de cet enzyme etait nettement augmentee dans la fraction myeline (produit glial) et legerement augmentee dans la fraction synaptosomique (neuronale) apres traitement chronique par la PHT (4 fois/jour pendant 7 jours). Ces resultats suggerent que la PHT affecte de fa¸on differente les 2 formes (gliale et neuronale) de l'enzyme Na-, K+-ATPase, Les auteurs discutent l'importance possible de cette hpothese par rapport aux properietes anticonvulsives et excitatrices de la PHT. Le traitement chronique par la PHT (2 fois/jour et 4 fois/jour pendant 7 jours) augmentait a la fois le contenu en DNA et l'activite du marqueur glial anhydrase carbonique. II y avait aussi une augmentation de l'activite de l'enyzme mitochondrial HCO3--ATPase. Ces duex enzymes ont intimement impliques dans la regulationd u transport HCO3--CL-a travers les cellules gliales et les membranesmitochondriales, et ces resultats suggerent que la PHT peut ameliorer les processus regulateurs gliaux. Cette possibilie d'augmenter la regulation gliale des cations et anions des liquides extra-cellulaires fournit des aper¸us nouveaux et importants sur le mecanisme del'action anticonvulsive de la PHT.