Abstracts

Rationale: At therapeutic concentrations, certain antiepileptic drugs (AEDs) such as phenobarbital (PB) and phenytoin (PHE) induce neuronal apoptosis in the developing brain, while others such as lamotrigine (LTG) and leviteracetam (LEV) do not. In the rat, this neurotoxicity is especially pronounced at postnatal days (P) 6-8, a period encompassing the "brain growth spurt," which occurs in humans during the third trimester of gestation and early infancy. Several cortical and subcortical areas are targets of this proapoptotic action, including regions that play key roles in seizure control and motor function. We therefore assessed the impact of early postnatal exposure to AEDs on seizure thresholds and rotarod performance later in life. Methods: Sprague-Dawley rat pups were treated with: PB (75mg/kg, ip on P7, followed by 25mg/kg, ip from P8-14) or PHE (50mg/kg, ip, from P7-14) and then tested for seizures in response to varying doses of pentylenetetrazol (PTZ, 25-50mg/kg, ip) to assess seizure threshold when they reached adulthood (P60). Seizure incidence, severity and latency to myoclonic or clonic seizure, was measured as a function of dose of PTZ. A separate cohort of animals was tested at P120 on the accelerating rotarod (0-50 RPM, over 300 sec) and latency to fall was recorded. Results: The PB and PHE exposed animals exhibited a leftward shift in the dose-response function for seizure incidence. The median dose of PTZ required to provoke myoclonic jerks in controls was 32.5mg/kg, and in PB- and PHE-exposed animals, 27.5mg/kg. The latency to fall off the rotarod in PHE-exposed animals (32 sec) was reduced as compared to controls (117 sec). This deficit persisted over 10 consecutive trials. Rotarod testing of PB-exposed animals is in progress. Conclusions: These data suggest that exposure to subacute treatment of rat pups with PB or PHE during the neonatal period has a long-term influence on seizure susceptibility and motor coordination in adulthood, perhaps reflecting impairment in the maturation of neural circuits that control epiletogenesis and motor function. One candidate circuit is the striato-nigral GABA system, a system responsible for postural control and resistance to seizure generation. The fact that the dorsal striatum is especially vulnerable to the proapoptotic effect of neonatal treatment with PB and PHE, makes it tempting to speculate that compromised function in the striato-nigral system contributes to the adverse effects we observed. If this is the case, we predict that these long-term adverse effects will not be associated with AED treatment devoid of proapoptotic actions. Experiments are currently in progress using LTG (20mg/kg) and LEV (100mg/kg) to test this hypothesis. Support: T32DA007291, R01NS020576, and Glaxo-Smith-Klein