Abstracts

We have previously demonstrated the neuroprotective effects of repeated brief seizures evoked by low-intensity (minimal) electroconvulsive shock (ECS) in adult rats. However, we do not know if repeated brief seizures can also exert a neuroprotective action in neonatal animals. In the present study, we evaluated the impact of repeated ECS-induced seizures on the programmed cell death (PCD) which has been demonstrated to occur in the neonatal rat brain in response to exposure to the NMDA receptor antagonist, MK-801. We also examined the interaction between ECS and exposure to valproic acid (VPA) and levetiracetam, two anticonvulsant agents. Sprague-Dawley male and female rat pups between P5 and P8 were used in all experiments. was applied to rat pups via corneal electrodes (200msec, 35mA) which induced minimal motor seizures lasting 5-10 sec. A single treatment session consisted of 3 ECS seizures, given at 0, 30 and 60 min. Control (sham-treated) rats received the same handling but no current was passed through the electrodes. Either (0.5mg/kg), (400mg/kg) or (1000mg/kg) were injected intraperitoneally 24hr prior to sacrifice. ECS treatment sessions were given at varying intervals (6-24hr apart), before and/or during the drug exposure. TUNEL assay and Fluoro-Jade B staining were used to detect neurodegeneration in various brain regions. ECS (3 daily sessions or 3 sessions/day) consistently and significantly reduced MK-801-induced neuronal cell death in striatum (30% reduction) and thalamus (25% reduction). However, the ECS treatment did not significantly attenuate valproic acid-induced neurodegeneration in the same brain regions. Surprisingly, levetiracetam did not induce neuronal death either in the presence or absence of ECS. Our data indicate that repeated brief seizures can attenuate the PCD induced by MK-801 in the neonatal brain. However, the ECS treatment did not reduce neuronal cell damage induced by valproic acid. Our results suggest that in the developing brain, 1) ECS can exert a neuroprotective action and 2) this action may depend on the mechanism by which PCD is induced. Levetiracetam is distinct from other anticonvulsant drugs in its lack of pro-apoptotic action. The functional impact of the regional changes in PCD in the developing brain will be evaluated by testing animals for cognitive function as they mature. (Supported by NIH grants NS 20576, MH 02040, NS 041231, Epilepsy Foundation predoctoral fellowship)