Topiramate blocks perinatal hypoxia-induced seizures in rat pups.
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.
Koh
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Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jensen
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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
D000927:Anticonvulsants; D003292:Convulsants; D018091:Receptors, AMPA; D000077236:Topiramate; D005632:Fructose; D007608:Kainic Acid