Abstracts

Rationale: Stroke in neonates and infants presents with seizures that are frequently treated with phenobarbital. We hypothesized that anticonvulsants attenuate ischemic injury, however, age- and injury-dependant differences in gene expression determine the brain s response to GABA enhancement. Methods: P12 CD1 mice received common carotid ligation, and immediate phenobarbital (30 mg/kg or 60 mg/kg i.p.) or vehicle, and acute seizures were scored. 5 doses of BrdU (50 mg/kg/dose) were administered i.p. between P18-P20, cognitive testing done between P32-P37, and mice were perfused at P40. Brain atrophy was quantified, and DG BrdU-labeled cells counted. Mice injected with 30 mg/kg or 60 mg/kg phenobarbital or vehicle i.p. had respiratory rates observed 2 hours later and blood levels measured 4, 12, 24 or 36 hours. Results: 33.3% (8/24) of injured mice receiving 30 mg/kg phenobarbital seized (median seizure score=0, range 0-20, p<0.01 versus vehicle), 70% (14/20) of injured mice receiving 60 mg/kg phenobarbital (median seizure score=7.5, range 0-15, p=0.034 versus vehicle) and 63.6% (14/22) of injured mice given vehicle (median seizure score=16, range 0-75) displayed seizures. Hippocampal and hemispheric atrophy in 30 mg/kg treated injured mice were 47.3% and 20.3% (N.S. and p<0.01 versus vehicle), 67.2% and 46.7% in 60 mg/kg treated (both p=N.S. versus vehicle), and 60.2% and 42.9% in vehicle-treated injured mice. Counts of rears during open-field testing in mice receiving 60 mg/kg of phenobarbital were significantly less than the other two groups and less than uninjured animals. Additionally, vehicle and 60 mg/kg PB-treated injured animals both spent significantly less time rearing than their uninjured counterparts. Between session habituation was impaired in the vehicle and 60 mg/kg treated injured groups, while 30 mg/kg restored habituation in injured animals. The percent decrease in BrdU counts (ipsilateral to contralateral) showed a trend for a greater decrease in the 60 mg/kg group. The 60 mg/kg dose eliminated the significant correlations between seizures and hippocampal injury. Peak blood levels were 25.4 2.0 mg/dl (n=2) at 4 hrs after 30 mg/kg and 46.9 1.6 mg/dl (n=2) after 60 mg/kg. Respiratory rates were not significantly different between groups.