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Neurotoxicity of phenytoin administered to newborn mice on developing cerebellum
H Ohmori1, T Kobayashi, M Yasuda
1Department of Anatomy, Hiroshima University School of Medicine, Japan.
Insights
Phenytoin (PHT) exposure during early development impaired motor skills and caused significant cerebellar damage in mice. Neonatal PHT administration led to reduced brain and cerebellum size, indicating neurotoxicity.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Phenytoin (PHT) is an anticonvulsant medication.
- Cerebellar development is crucial for motor function and coordination.
- Potential neurotoxic effects of PHT on developing brains require investigation.
Purpose of the Study:
- To investigate the neurotoxic effects of phenytoin on cerebellar development in neonatal mice.
- To assess the impact of PHT exposure on motor reflexes and cerebellar histology.
Main Methods:
- Neonatal Jcl:ICR mice received daily oral doses of 50 mg/kg phenytoin (PHT) from postnatal days 2-14.
- Plasma PHT concentrations were monitored during treatment.
- Motor function (walking reflex, negative geotaxis) and cerebellar histology were evaluated.
- Brain and cerebellar weights were measured at postnatal day 56.
Main Results:
- Treated mice exhibited poorly developed walking reflex and negative geotaxis on postnatal day 14.
- A significant increase in pyknotic cells in the external granular layer (EGL), particularly in the vermis, was observed.
- Plasma PHT levels reached a steady state of 34-36 µg/ml by the third day of treatment.
- Total brain weight, cerebellum size, and cerebellar weight were significantly reduced in PHT-treated mice by postnatal day 56.
Conclusions:
- Neonatal oral administration of phenytoin induces significant neurotoxic damage to the developing cerebellum.
- PHT exposure during a critical developmental window impairs motor function and cerebellar growth.
- These findings highlight the potential risks of PHT in early life exposure.
Abstract:
To examine the neurotoxic effects of phenytoin (PHT) on cerebellar development, we administered 50 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-14 and determined plasma PHT concentrations at designated intervals during the administration period. In the treated group, walking reflex and negative geotaxis were poorly developed on postnatal day 14. Pyknotic cells in the external granular layer (EGL) significantly increased and were prominent in the vermis area compared with controls on postnatal day 14. Plasma PHT levels were 34-36 micrograms/ml on the 3rd day of PHT treatment and approached a steady-state situation. Total brain weight, size of the cerebellum, and cerebellar weight were significantly reduced in the treated group on postnatal day 56. Accordingly, oral administration of PHT in the neonatal period induced neurotoxic damage on the developing cerebellum.