Brain Maturation Following Administration of Phenobarbital, Phenytoin, and Sodium Valproate to Developing Rats or to Their Dams: Effects on Synthesis of Brain Myelin and Other Subcellular Membrane Proteins

Abstract: The anticonvulsant drugs phenobarbital, phenytoin, sodium valproate, and phenytoin-sodium valproate in combination were administered daily to (a) pregnant rats starting on the 5th day after conception, and continued through 17 days postpartum, or (b) to developing rats between 3 and 17 days of age. Each drug was prepared in water and administered at either a therapeutic dose (TD), three times therapeutic dose (³TD), or 9TD. Drug administration had no discernible effect on litter size or sex ratio in the offspring; however, phenobarbital administration to dams caused small but significant reductions in birth weights. Body weights of developing rats treated with anticonvulsant drugs either via dams or directly by intraperitoneal injection lagged behind controls. At 20–24 days of age the brain weights of the offspring of phenobarbital (9TD)-exposed dams lagged control weights by 5% whereas brain weights in the offspring of the other treated groups were indistinguishable from controls. In contrast, administration of phenobarbital directly to developing rats caused no significant brain weight deficits whereas significant deficits were observed with phenytoin (9TD), sodium valproate (9TD), and phenytoin-sodium valproate (9TD) in combination. At 20–24 days of age the relative incorporation of radioactive leucine into purified myelin and crude nuclear proteins of drug-treated rats or the offspring of drug-treated dams was reduced by 10–20% in all cases. Dose-related differences were not observed however, and the effects of phenytoin and sodium valproate in combination approximated those of phenytoin administered alone.