Talampanel suppresses the acute and chronic effects of seizures in a rodent neonatal seizure model

Abstract

To test the efficacy of the novel candidate anticonvulsant talampanel (GYKI 53773) in a rodent model of hypoxic neonatal seizures. Talampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid subtype of the glutamate receptor (AMPAR). We have previously shown that AMPARs play a critical role in the generation of acute seizures and later-life seizure susceptibility in this model of neonatal seizures. Seizures were induced in postnatal day (P) 10 Long-Evans rat pups by a 15 min exposure to global hypoxia. Acute seizure activity at P10 and subsequent susceptibility to seizure-induced neuronal injury with a "second-hit" kainate-induced seizure at P30-31 were compared between animals receiving talampanel (1, 5, 7.5, or 10 mg/kg) intraperitoneally (i.p.) versus saline vehicle treatment. Talampanel treatment suppressed seizures in a dose-dependent manner, with maximal effect at 7.5 and 10 mg/kg. In addition, talampanel treatment 30 min before hypoxia prevented later-life increases in seizure-induced neuronal injury as assessed by in situ DNA nick end-labeling (ISEL). We have previously demonstrated efficacy of other AMPAR antagonists such as NBQX and topiramate in this model. The present finding shows that the novel agent talampanel, under evaluation as an antiepileptic drug in children and adults, may have clinical potential in the treatment of neonatal seizures, particularly those occurring in the context of hypoxic encephalopathy.