Abstracts

Rationale: The most common cause of neonatal seizures is hypoxic-ischemic encephalopathy, and can be refractory to conventional anticonvulsant drugs (AEDs). To date, there are no clinically available agents that are specifically designed for parenteral use in neonatal seizures. Levetiracetam (LEV) is a newer AED and binds to a synaptic vesicle protein 2A (SV2A). Recently, LEV became available for parenteral use, and has been proposed as a potential therapy for neonatal seizures. However, there is little data regarding its efficacy in preclinical neonatal seizure models and the precise mechanism of action of LEV has not been fully elucidated. Methods: Postnatal day (P) 10 rat pups were pretreated by intraperitoneal (i.p.) injection 60 min prior to global hypoxia (scaled exposure from 7-4% O₂ over 15 min) with vehicle (PBS) or LEV at 10, 25, or 50 mg/kg. Seizure episodes were recorded by a blinded investigator and electroencephalographic (EEG) recordings were obtained and analyzed for the presence of seizure activity during hypoxia. An EEG seizure was defined by paroxysmal, rhythmic discharges displaying high amplitude diffuse fast activity lasting more than 3 seconds in duration. The developmental regulation of SV2A was examined in rat brain tissue by western blot analysis. Statistical comparisons were performed by one-way ANOVA followed by post hoc Bonferroni t-test. Results: Vehicle treated pups experienced episodes of tonic-clonic trunk and head movements, with an average total duration of 341.8±28.4 sec (n=18). LEV treatment resulted in a significant decrease in seizure duration at 25 mg/kg (175.0±33.8 sec, n=8, p=0.01) and at 50 mg/kg (124.4±21.2 sec, n=19, p<0.001). The cumulative duration of ictal discharges was significantly less in groups treated with LEV at 25 mg/kg (175.8±17.6 sec, n=6, p=0.041) and at 50 mg/kg (154.7±32.3 sec, n=10, p=0.005), as compared to vehicle (347.1±41.7 sec, n=9). Western blot quantification of SV2A in the rat hippocampus and cortex at different postnatal ages, demonstrates that, at P5, P10, P14, SV2A is expressed, but at significantly lower levels than at P21 (p<0.05 at hippocampus, overall p=0.020 at cortex) and P40(p<0.001 at hippocampus, overall p=0.020 at cortex).