title: Topiramate blocks perinatal hypoxia-induced seizures in rat pups.
abstract: Neonatal seizures caused by hypoxia can be refractory to conventional anticonvulsants. Currently, there is no effective postnatal intervention for newborn infants with hypoxic encephalopathy to prevent brain injury and long-term neurologic sequelae. We previously developed a rat model of perinatal hypoxia-induced seizures with subsequent long-term increases in seizure susceptibility and showed that these epileptogenic effects are selectively blocked 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 topiramate during acute hypoxia, there were no long-term increases in susceptibility to kainate-induced seizures and seizure-induced neuronal injury. Our results suggest that topiramate may have clinical potential as a therapeutic agent for refractory seizures in human neonates.
authors.affiliation: Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Koh
authors.forename: F E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000833:Animals, Suckling; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D003292:Convulsants; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018091:Receptors, AMPA; D000077236:Topiramate; D005632:Fructose; D007608:Kainic Acid