Developmental neurotoxicity of phenytoin on granule cells and Purkinje cells in mouse cerebellum

Phenytoin (PHT) is a primary antiepileptic drug. Cerebellar malformations i n human neonates have been described following intrauterine exposure to PHT . The neonatal period of development in the cerebellum in mice corresponds to the last trimester in humans. To examine the neurotoxic effects of PHT i n the developing cerebellum, we administered PHT orally to newborn mice onc e a day during postnatal days 2-4. We observed many apoptotic cells in the external granular layer (EGL) on postnatal day 5, labeled cells in the EGL still remaining 72 h after labeling with 5-bromo-2'-deoxyuridine, and EGL t hicker than that in the control on postnatal day 14. These results showed t hat PHT induced cell death of external granule cells and inhibited migratio n of granule cells in cerebella. In specimens immunostained with antibody a gainst inositol 1,4,5-trisphosphate receptor type 1, Purkinje cells in the treated group had poor and immature arbors, and partially showed an irregul ar arrangement. The motor performance of the treated mice in a rotating rod test was impaired, although there were no changes in muscular strength or in walking pattern at the period of maturity. These findings indicate that PHT induces neurotoxic damage to granule cells and Purkinje cells in the de veloping cerebellum and impairs selected aspects of motor coordination abil ity.