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Neurotoxic effects of phenytoin on postnatal mouse brain development following neonatal administration
T Hatta1, H Ohmori, T Murakami
1Institute of Health Sciences, Hiroshima University School of Medicine, Japan. thatta@mcai.med.hiroshima-u.ac.jp
Insights
Prenatal phenytoin (PHT) exposure can harm developing brains. This study shows PHT reduces brain weight and impairs motor function in newborn mice, indicating developmental neurotoxicity.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Phenytoin (PHT) is an anticonvulsant with known risks of developmental neurotoxicity.
- Prenatal PHT exposure in humans is linked to brain malformations and psychomotor dysfunction.
- Neonatal mouse CNS development models human third-trimester development.
Purpose of the Study:
- To investigate the neurotoxic effects of PHT on postnatal brain development in mice.
- To assess the impact of PHT on brain growth and early motor functions.
Main Methods:
- Newborn mice received daily PHT doses (10-35 mg/kg) on postnatal days 2-4.
- Brain weights (total, cerebrum, cerebellum, brain stem) were measured from PD 5-21.
- Early motor functions (head elevation, pelvic elevation, pivoting, crawling, righting reflex) were evaluated.
Main Results:
- Significant reductions in total brain, cerebral, and cerebellar weights were observed in mice treated with 25 or 35 mg/kg PHT.
- High-dose PHT treatment (25 or 35 mg/kg) impaired locomotor abilities and righting reflex on PD 5.
- Brain PHT concentrations exceeded plasma levels by day 3 of treatment across all dose groups.
Conclusions:
- Phenytoin exhibits neurotoxic effects on postnatal brain development in mice.
- These findings highlight the potential for PHT-induced developmental neurotoxicity and inform the evaluation of psychomotor development in exposed children.
Abstract:
Phenytoin (PHT) is a commonly used anticonvulsant drug. It has been reported that children exposed prenatally to PHT have brain malformations and psychomotor dysfunction. The neonatal development of the central nervous system (CNS) in mice corresponds to the last trimester in humans. To examine the neurotoxic effects of PHT on postnatal brain development, we administered PHT at doses of 10, 17.5, 25, or 35 mg/kg to newborn mice once a day during postnatal days (PD) 2-4. These dose levels result in plasma levels corresponding to the therapeutic ranges in humans. We measured the weight of total brain, cerebrum, cerebellum, and brain stem on PD 5 through 21, and examined early motor functions including head elevation, elevation of pelvis, pivoting, crawling, and righting reflex . Total brain weight, cerebral weight, and cerebellar weight in the group treated with 25 or 35 mg/kg were significantly reduced compared to controls from PD 5 to 21. Mice treated with PHT at 25 or 35 mg/kg showed decreased locomotor abilities and righting reflex on PD 5. In all phenytoin treatment groups, phenytoin levels in the brain were higher than those in the plasma on the third day of PHT treatment. We thus observed neurotoxic effects of PHT on postnatal brain development in mice. Our present data may provide useful implications for the management of PHT-induced developmental neurotoxicity and evaluation of psychomotor development in children exposed to PHT during the late fetal period.