Abstracts

Several AEDs induce pronounced apoptotic neuronal death in specific brain regions in the neonatal rat (Bittigau et al, PNAS,2002). Moreover, AEDs in doses subthreshold for causing cell death in the neonatal brain, can cause substantial cell death when given in combination with other AEDs. Although newer AEDs such as topiramate (TPM) and levetiracetam (LEV) cause little or no cell death in neonatal rats when given alone, neither has been examined for effects on cell death when combined with other AEDs. This is of particular concern because these drugs are frequently used in polytherapy. Therefore, we examined the neurotoxicity of TPM and LEV alone and in combination with phenytoin (PHT) in rat pups. We also examined the effect of carbamazepine (CBZ), a drug often used during pregnancy and childhood., TPM (20, 40, 80mg/kg), LEV (250, 500, 1000mg/kg) or CBZ (25, 50, 100mg/kg), was given to Sprague-Dawley rat pups at postnatal day 7, 24h prior to sacrifice. The following doses were also tested in combination with 50 mg/kg PHT: TPM (20, 40, 80mg/kg); LEV (500mg/kg); CBZ (25, 50mg/kg). In addition, LEV (250, 500mg/kg) was tested in combination with CBZ (50mg/kg). Cell death was evaluated by TUNEL and Fluoro-Jade B staining in 20micron coronal brain sections throughout the forebrain and midbrain., Although TPM (20-80mg/kg) alone did not induce cell death, it significantly enhanced cell death induced by PHT, even at the lowest dose. CBZ alone did not cause cell death up to 50mg/kg, but when combined with PHT, 50mg/kg (but not 25mg/kg) CBZ significantly enhanced PHT-induced cell death. Cell death was most marked in thalamus and striatum. LEV (250-1000mg/kg) alone did not induce cell death, and doses up to 500 mg/kg were without effect on PHT-induced cell death. No detectable cell death resulted from the combination of LEV (250mg/kg) with CBZ (50mg/kg)., In comparison to most traditional AEDs, CBZ, TPM and LEV are relatively devoid of a pro-apoptotic action in the developing brain, when administered in a dose range equivalent to, or higher than, the therapeutic range for seizure control. However, our data indicate that they exhibit distinct profiles of interaction with PHT. Whereas both TPM and CBZ significantly exacerbated PHT-induced cell death, LEV was devoid of this effect. Our data underscore the importance of evaluating the safety of AEDs given in combinations and not merely extrapolating from the effects of exposure to single drugs. Our data suggest that the combination of CBZ and LEV minimizes neurotoxicity in the developing brain and may therefore hold promise as a potential treatment of choice for AED therapy in pregnancy, preterm infants and neonates., (Supported by Epilepsy Foundation predoctoral fellowship, Partnership for Pediatric Epilepsy Research and NIH (NS 20576, MH 02040, NS 041231, HD047890).)