Abstracts

Hypoxic encephalopathy is a major cause of neonatal seizures, and can lead to long term neurologic deficit and epilepsy. Neonatal seizures can be refractory to conventional AED medication. AMPARs are overexpressed on cortical neurons in the neonatal rat and term human, when the susceptibility to hypoxic seizures is highest (J. Comp. Neur. 2006; 497:42). We have shown that the AMPA subtype of neuronal glutamate receptors in cortex and hippocampus play a critical epileptogenic role in a rodent model of neonatal seizures (J. Neurosci. 2005; 25:3442), and AMPAR antagonists such as NBQX and topiramate effectively suppress the acute and long term epileptogenic effects of hypoxia in the perinatal rodent (Ann. Neurol. 2001; 50:366; Epilepsia 2004; 45:569). Here we evaluated the efficacy of talampanel (GYKI-53773), a novel orally-available non-competitive AMPAR antagonist in our rodent model., P10 rat pups were exposed to global hypoxia per our previous protocols (J. Neurosci. 2001; 21:8154). Rats were pretreated i.p. with talampanel or vehicle 30 minutes prior to hypoxia and seizure time and severity were recorded by videotape and scored blinded. A second outcome measure was evaluated by assessing susceptibility of rats to KA-induced seizures 20 days (P30) after they were exposed to hypoxia. KA was administered i.p. (10mg/kg) and seizure activity was recorded over a 3-hour period. Rats given KA on P30 were killed on P33 by transcardiac perfusion with 4% paraformaldehyde. Each brain was removed, postfixed, cyroprotected in 20% sucrose overnight, and mounted onto a freezing microtome. To quantify DNA fragmentation, counts of positively stained cells per 12,500[micro]m² in CA1, CA3 and amygdala were made as previously described (Ann. Neurol. 2001; 50:366)., Acute hypoxia-induced seizures at P10 were suppressed by talampanel in a dose-related manner. Anticonvulsant activity was maximal at 7.5 and 10mg/kg, where seizures were blocked 74.6% at 10mg/kg (25.4 [plusmn] 7.3, n = 17; p [lt]0.001) and 86.7% at 7.5mg/kg (13.3[plusmn]3.2, n =17; p [lt]0.001). Rats pretreated with vehicle prior to hypoxia showed significantly more neuronal injury in amygdala following KA-induced seizure at P30 than did nonhypoxic controls or rats pretreated with talampanel (7.5 and 10 mg/kg) prior to hypoxia at P10 (p[lt]0.001, one-way ANOVA)., Talampanel exhibited a dose-dependent effect on hypoxia-induced hypoxic seizures in the immature rat. Futhermore, acute talampanel treatment during hypoxia protected the rats from later life increases in seizure susceptibility that are observed in vehicle treated hypoxic controls. These data suggest talampanel may have clinical potential in the treatment of neonatal seizures., (Supported by Epilepsy Project, IVAX, and NINDS RO1 NS31718.)