Therapeutic doses of topiramate are not toxic to the developing rat brain.
Antiepileptic drugs (AEDs) used to treat seizures in pregnant women, infants, and young children may cause cognitive impairment. One of the implicated mechanisms is enhancement of apoptotic neuronal death, which occurs physiologically in the developing brain. We investigated whether topiramate, one of the newer antiepileptic drugs, has neurotoxic properties in the developing rat brain. Topiramate slightly but significantly enhanced apoptotic neuronal death in the 7-day-old rat brain at doses of 50 mg/kg and above. These doses are several folds higher than reported ED(50) doses in infant rodent seizure models that respond to topiramate. Electron microscopy confirmed that dying neurons following topiramate treatment displayed the same morphological features as neurons undergoing physiological cell death during development. When compared to the neurotoxicity profile of phenytoin, valproate, and phenobarbital, the separation between the effective anticonvulsant dose and the neurotoxic dose was greater for topiramate and the neurotoxic effect was lower.
Glier
Carmen
C
Department of Pediatric Neurology, Charite, Virchow Clinics, Humboldt University, 13353 Berlin, Germany.
Dzietko
Mark
M
Bittigau
Petra
P
Jarosz
Bozena
B
Korobowicz
Elzbieta
E
Ikonomidou
Chrysanthy
C
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000031:analogs & derivatives* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D010672:Phenytoin / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000077236:Topiramate; D014635:Valproic Acid / Q000633:toxicity
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid; D010672:Phenytoin; D010634:Phenobarbital