Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.
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.
Bittigau
Petra
P
Department of Pediatric Neurology, Children's Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Sifringer
Marco
M
Genz
Kerstin
K
Reith
Ellen
E
Pospischil
Dana
D
Govindarajalu
Suresh
S
Dzietko
Mark
M
Pesditschek
Stefanie
S
Mai
Ingrid
I
Dikranian
Krikor
K
Olney
John W
JW
Ikonomidou
Chrysanthy
C
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
D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D003975:Diazepam; D010634:Phenobarbital