PHENYTOIN PRETREATMENT PREVENTS HYPOXIC-ISCHEMIC BRAIN-DAMAGE IN NEONATAL RATS

This study was performed to investigate whether the anticonvulsant phe nytoin has neuroprotective effect in a model of hypoxia-ischemia with neonatal rats. The left carotid artery of each rat was ligated, follow ed by 3 h of hypoxic exposure (8% O-2) in a temperature-regulated envi ronment (36 degrees 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 d ose-dependent manner (3, 10, and 30 mg/kg i.p.) when administered befo re the hypoxic episode. Phenytoin administered during or after hypoxia did not alter hypoxic brain damage significantly. A parallel experime nt using histological examination of frozen brain sections demonstrate d less brain infarction after phenytoin treatment (30 mg/kg i.p.). In an additional experiment measuring breakdown of an endogenous brain ca lpain substrate, spectrin, phenytoin treatment reduced this measure of early cellular damage. Our results indicate that pretreatment with ph enytoin is neuroprotective at a plasma phenytoin concentration of appr oximately 12 mu g/ml. These results are consistent with the hypothesis that blockade of voltage-dependent sodium channels reduces brain dama ge following ischemia.