Phenytoin pretreatment prevents hypoxic-ischemic brain damage in neonatal rats

This study was performed to investigate whether the anticonvulsant phenytoin has neuroprotective effect in a model of hypoxia-ischemia with neonatal rats. The left carotid artery of each rat was ligated, followed by 3 h of hypoxic exposure (8% O 2) in a temperature-regulated environment (36°C). Two weeks later, brain damage was assessed by measuring loss of brain hemisphere weight. Phenytoin had no effect on body temperature or plasma glucose, but attenuated brain damage in a dose-dependent manner (3, 10, and 30 mg/kg i.p.) when administered before the hypoxic episode. Phenytoin administered during or after hypoxia did not alter hypoxic brain damage significantly. A parallel experiment using histological examination of frozen brain sections demonstrated less brain infarction after phenytoin treatment (30 mg/kg i.p.). In an additional experiment measuring breakdown of an endogenous brain calpain substrate, spectrin, phenytoin treatment reduced this measure of early cellular damage. Our results indicate that pretreatment with phenytoin is neuroprotective at a plasma phenytoin concentration of approximately 12 μg/ml. These results are consistent with the hypothesis that blockade of voltage-dependent sodium channels reduces brain damage following ischemia.