Abstracts

Recent data indicate that several antiepileptic drugs (AEDs) induce pronounced apoptotic neuronal death in specific brain regions during the first two postnatal weeks in rat (Bittigau et al., PNAS, 99:15089, 2002). The corresponding period in humans stretches from late gestation through infancy. Since excessive neuronal loss in late prenatal or early postnatal development may cause long-term adverse effects, the identification of AEDs devoid of this deleterious action is a top priority. Here we compared levetiracetam, carbamazepine, valproate, and phenytoin, given to neonatal rats, for their effects on cell death in several brain regions. In addition, we examined effects on cell death when levetiracetam or carbamazepine was given in combination with phenytoin. Levetiracetam (500, 1000, 1500mg/kg) or carbamazepine (25, 50, 100mg/kg) was administered to Sprague-Dawley rat pups at postnatal day 7 (PD7), 24hr prior to sacrifice. For purposes of comparison, we administered 3 drugs previously reported to cause marked cell death in PD7 rats: phenytoin (50mg/kg), valproate (400mg/kg) and MK801 (0.5mg/kg). The following drug combinations were also tested: levetiracetam (500 or 1500mg/kg) + MK801 (0.5mg/kg); levetiracetam (500 or 1000mg/kg) + phenytoin (50mg/kg); carbamazepine (50mg/kg) + phenytoin (50mg/kg). Cell death was evaluated in 20micron coronal brain sections by TUNEL assay and Fluoro-Jade B staining. Phenytoin, valproate, and MK801 each induced substantial cell death in specific brain areas including thalamus, cortex and striatum, as previously reported by Bittigau et al. In contrast, neither levetiracetam nor carbamazepine caused cell death even when given in high doses. However, when combined with phenytoin (50mg/kg), carbamazepine (50mg/kg) significantly exacerbated the cell death in thalamus, cortex and striatum, whereas levetiracetam (500 or 1000mg/kg) had no effect on cell death induced by either phenytoin or MK801 in any brain regions. Carbamazepine caused marked sedation whereas levetiracetam was without sedating effects. This is the first evidence indicating that levetiracetam and carbamazepine do not induce cell death in the neonatal rat brain, demonstrating that induction of cell death is not a consistent feature of AED action in neonates. Furthermore, since carbamazepine exacerbated the cell death induced by phenytoin, while levetiracetam did not, levetiracetam may be an especially promising candidate for monotherapy and add-on treatment for use in pregnant women and in neonates. (Supported by a Predoctoral Fellowship from the Epilepsy Foundation, and a research grant from the Partnership for Pediatric Epilepsy Research (administered through the Epilepsy Foundation) and NIH grants R01 NS20576, K01 MH02040, U10 HD047890.)