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Abstract
Antiepileptic drugs (AEDs) induce apoptotic neuronal death in specific regions of rat brain during the first two postnatal weeks; this developmental neurotoxicity may contribute to adverse behavioral outcomes. In this project, four studies examined the impact of seizures and/or AEDs or AED combinations on cell survival in the immature brain. (1) This study tested the hypothesis that repeated seizures will increase basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and/or brain-derived neurotrophic factor (BDNF) in specific brain areas in the neonatal period. Chronic seizures induced by electroconvulsive shock (ECS) did not change trophic factor protein levels in the 1st postnatal week, increased BDNF during the 2nd postnatal week, and increased both BDNF and FGF-2 during the 3rd postnatal week. These data contrast with seizure-induced upregulation of trophic factors in adults. (2) To identify AEDs with minimal risk of neurotoxicity in the developing brain, the pro-apoptotic effects of carbamazepine (CBZ), topiramate (TPM), and levetiracetam (LEV), alone or combined with phenytoin, were evaluated in several brain areas. CBZ (50mg/kg) and TPM (20–80mg/kg) did not induce cell death when given alone, but exacerbated phenytoin-induced apoptosis. LEV (250–1000mg/kg) neither induced apoptosis nor exacerbated apoptosis induced by phenytoin. LEV (250mg/kg) plus CBZ (50mg/kg) was the only combination identified that did not induce apoptosis. The latter drugs may be especially promising candidates for therapy of women during pregnancy, and for pre-term and neonatal infants. (3) The impact of pre-exposure to repeated seizures on drug-induced neuronal apoptosis was examined in the first postnatal week. Pre-exposure to 3 days of ECS treatment did not affect apoptosis induced by valproate, phenobarbital or phenytoin. However, ECS pre-exposure significantly attenuated neuronal death induced by the glutamate antagonist, MK801. These data suggest that ECS can be neuroprotective, depending upon the mechanism by which apoptotic cell death is induced. (4) Pilot studies of long-term behavioral effects of neonatal seizures or neurodevelopmental apoptosis were initiated. Rats exposed to ECS or MK801 as neonates were tested at PD30 and PD60 in several behavioral tasks; tests of spatial novelty and of anxiety appeared to be especially sensitive to changes induced by the neonatal treatments.
