TY - JOUR
T1 - Antiepileptic drugs and apoptotic neurodegeneration in the developing brain
AU - Bittigau, Petra
AU - Sifringer, Marco
AU - Genz, Kerstin
AU - Reith, Ellen
AU - Pospischil, Dana
AU - Govindarajalu, Suresh
AU - Dzietko, Mark
AU - Pesditschek, Stefanie
AU - Mai, Ingrid
AU - Dikranian, Krikor
AU - Olney, John W.
AU - Ikonomidou, Chrysanthy
PY - 2002/11/12
Y1 - 2002/11/12
N2 - 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.
AB - 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.
KW - Epilepsy
KW - Neurotrophins
KW - Rat
KW - Survival
UR - http://www.scopus.com/inward/record.url?scp=0037069448&partnerID=8YFLogxK
U2 - 10.1073/pnas.222550499
DO - 10.1073/pnas.222550499
M3 - Article
C2 - 12417760
AN - SCOPUS:0037069448
SN - 0027-8424
VL - 99
SP - 15089
EP - 15094
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -