Lippincott Williams & Wilkins, Inc., Philadelphia
Developmental Neurotoxicity of Phenytoin on Granule Cells and Purkinje Cells in Mouse Cerebellum
Article first published online: 25 DEC 2001
Journal of Neurochemistry
Volume 72, Issue 4, pages 1497–1506, April 1999
How to Cite
Ohmori, H., Ogura, H., Yasuda, M., Nakamura, S., Hatta, T., Kawano, K., Michikawa, T., Yamashita, K. and Mikoshiba, K. (1999), Developmental Neurotoxicity of Phenytoin on Granule Cells and Purkinje Cells in Mouse Cerebellum. Journal of Neurochemistry, 72: 1497–1506. doi: 10.1046/j.1471-4159.1999.721497.x
Abbreviations used: ABC, avidin-biotin-peroxidase complex; BrdU, 5-bromo-2′-deoxyuridine; EGL, external granular layer; IGL, internal granular layer; IP3R, inositol 1,4,5-trisphosphate receptor; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; ML, molecular layer; PHT, phenytoin; PN, postnatal day(s).
- Issue published online: 25 DEC 2001
- Article first published online: 25 DEC 2001
- Developmental neurotoxicity;
- Neonatal period;
- Mouse cerebellum;
- Inositol 1,4,5-trisphosphate receptor type 1;
- Motor coordination
Abstract: Phenytoin (PHT) is a primary antiepileptic drug. Cerebellar malformations in 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 in the developing cerebellum, we administered PHT orally to newborn mice once 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 thicker than that in the control on postnatal day 14. These results showed that PHT induced cell death of external granule cells and inhibited migration of granule cells in cerebella. In specimens immunostained with antibody against inositol 1,4,5-trisphosphate receptor type 1, Purkinje cells in the treated group had poor and immature arbors, and partially showed an irregular 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 developing cerebellum and impairs selected aspects of motor coordination ability.