Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Petra Bittigau, Marco Sifringer, Kerstin Genz, Ellen Reith, Dana Pospischil, Suresh Govindarajalu, Mark Dzietko, Stefanie Pesditschek, Ingrid Mai, Krikor Dikranian, John W. Olney, Chrysanthy Ikonomidou

Research output: Contribution to journalArticlepeer-review

579 Scopus citations

Abstract

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. β-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.

Original languageEnglish
Pages (from-to)15089-15094
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number23
DOIs
StatePublished - Nov 12 2002

Keywords

  • Epilepsy
  • Neurotrophins
  • Rat
  • Survival

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