Abstract: AIM: To explore the relationship between the developmental neurotoxicity (DNT) induced by prenatal phenytoin(DPH) exposure and free radicals and oxidative stress initiated in the embryonic brain. METHODS: PregnantWistar rats were administered DPH by gavage on gestation days (GD) 11-14 in doses of 0, 100, 200 mg·kg^-1 and or 40 mg·kg^-1 MT (melatonin). RESULTS: DPH treated dams showed a dose related decrease in weight gain throughout the treatment period. Offspring had significantly lowered birth weight along with increased mortality.During the neonatal period, the pups exposed in uterus to DPH showed a significant increase in pivoting locomotion, and delayed in air righting reflex and swimming development.As adults, these pups showed an increased ambulation, rearing, stereotype events and rotational behavior.Furthermore, prenatal DPH exposure resulted in a dose-response shift to the left for locomotor activity of F1 DPH pups after stimulated by 0.2 and 2.0 mg·kg^-1 apomorphine. CONCLUSION: Co-administration of MT and DPH to dams significantly antagonized or protected most of the postnatal adverse effects induced by prenatal DPH exposure in F1 pups, which suggest that DNT induced by prenatal DPH exposure may be evoked and mediated via oxidative stress.

Key words: phenytoin, melatonin, developmental neurotoxicity, oxidative stress, antagonism