Abstracts

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 extends from late gestation through early infancy. Since excessive neuronal loss in late prenatal or early postnatal development may contribute to long-term adverse effects, it is important to identify treatment regimens that are devoid of this deleterious action. Here we examined the effects of lamotrigine (LTG, 10-100 mg/kg) on cell death in several brain regions of neonatal rats. We also examined the effects of LTG given in combination with either phenytoin or MK801., LTG (10, 20, 30, 50, 100 mg/kg) was administered to Sprague-Dawley rat pups at postnatal day 7 (PD7), 24hr prior to sacrifice. The following drug combinations were also tested: LTG 10, 20 or 30 mg/kg + phenytoin (50mg/kg) and LTG (20mg/kg) + MK801 (0.5mg/kg). Phenytoin (50 mg/kg) and MK801 (0.5 mg/kg) given alone were also evaluated. Cell death was evaluated in 20 [mu]m coronal brain sections by TUNEL assay in several brain areas, including striatum, thalamus, multiple cortical regions and the hippocampus., LTG alone administered at doses of 10-30 mg/kg did not induce significant cell death. At a dose of 50 mg/kg, 50% of the animals showed increased cell death in thalamus. Administration of 100 mg/kg resulted in significant increase in cell death in all brain areas examined except frontal cortex. Combined application of LTG (20 mg/kg) with MK-801 resulted in an enhancement of the MK-801-induced cell death effect in multiple regions. A similar enhancement of phenytoin-induced cell death was observed in the presence of 30 mg/kg LTG. In contrast, the lower dose of LTG (20 mg/kg) significantly [italic]attenuated[/italic] the phenytoin-induced cell death. The lowest dose of LTG (10 mg/kg) was without effect., Our results indicate that therapeutic doses of LTG alone do not induce cell death in the neonatal rat brain in marked contrast to traditional AEDs such as phenytoin, valproate and phenobarbital. However, when given in combination with other pro-apoptotic agents LTG may potentiate cell death, depending upon the dose and the specific drug combination. This is similar to the profile we have observed with topiramate in other studies. However, a unique feature of LTG is its ability, in low doses, to attenuate the cell death induced by phenytoin. It will now be of interest to determine whether this protective action of LTG in the neonatal brain can also be seen when LTG is combined with other traditional AEDs., (Supported by GlaxoSmithKline Research Grant, the Epilepsy Foundation, and NIH grants MH02040, U10 HD047890.)