Topiramate blocks perinatal hypoxia-induced seizures in rat pups

Neonatal seizures caused by hypoxia can be refractory to conventional antic onvulsants. Currently, there is no effective postnatal intervention for new born infants with hypoxic encephalopathy to prevent brain injury and long-t erm neurologic sequelae. We previously developed a rat model of perinatal h ypoxia-induced seizures with subsequent Ion-term increases in seizure susce ptibility and showed that these epileptogenic effects are selectively block ed by the alpha -amino-3-hydoxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione. Using this model of perinatal seizures, we evaluated the efficacy of topiramate, a structurally novel anticonvulsant drug recently shown to attenuate AMPA/ kainate currents. Topiramate effectively suppressed acute seizures induced by perinatal hypoxia in a dose-related manner with a calculated ED50 of 2.1 mg/kg, i.p. Furthermore, in animals that had seizures suppressed by topira mate during acute hypoxia, there were no long-term increases in susceptibil ity to kainate-induced seizures and seizure-induced neuronal injury. Our re sults suggest that topiramate may have clinical potential as a therapeutic agent for refractory seizures in human neonates.