title: Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.
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. beta-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.
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Bittigau
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Genz
authors.forename: Ellen
authors.initials: E
authors.lastname: Reith
authors.forename: Dana
authors.initials: D
authors.lastname: Pospischil
authors.forename: Suresh
authors.initials: S
authors.lastname: Govindarajalu
authors.forename: Mark
authors.initials: M
authors.lastname: Dzietko
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pesditschek
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mai
authors.forename: Krikor
authors.initials: K
authors.lastname: Dikranian
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D017931:DNA Primers; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics; D010634:Phenobarbital / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D003975:Diazepam; D010634:Phenobarbital