Phenytoin reduces neonatal hypoxic-ischemic brain damage in rats

We investigated the possible protective effect of phenytoin on hypoxic-ischemic brain damage in neonatal rats. Six-day-old rats underwent ligation of the left carotid artery followed by exposure to an 8% oxygen atmosphere for 2.5 hrs. We sacrificed the animals 72 hrs later and assessed the hypoxic-ischemic brain damage histologically. Phenytoin (50 mg/kg), administered intraperitoneally 1 hr before the hypoxia, reduced hypoxic-ischemic infarction in the cerebral cortex and striatum, and attenuated neuronal necrosis in the hippocampus. The plasma concentration of phenytoin after injection was 11.1 +/- 1.9 micrograms/ml (mean +/- S.E.M.) at 1 hr and 22.9 +/- 1.4 micrograms/ml at 4 hrs. Percent volumes of the infarction calculated by dividing the sum of damaged areas by the total area in serial coronal sections were 79 +/- 3% (mean +/- S.E.M.) in vehicle controls versus 13 +/- 6% in phenytoin-treated pups in the cerebral cortex, and 79 +/- 4% in vehicle controls versus 12 +/- 5% in phenytoin-treated pups in the striatum. We semiquantitatively investigated the hypoxic-ischemic change in 5 hippocampal areas: dentate gyrus, CA4, CA3, CA1, and subiculum, in the dorsal hippocampus. Pre-hypoxic treatment with phenytoin reduced hypoxic-ischemic damage in all areas examined. When phenytoin was administered immediately after the hypoxia, there was no difference between vehicle-injected controls and phenytoin-treated pups. These results demonstrate that phenytoin can reduce neonatal hypoxic-ischemic brain damage.