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....

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Published in:Proceedings of the National Academy of Sciences - PNAS 2002-11, Vol.99 (23), p.15089-15094
Main Authors: Bittigau, Petra, Sifringer, Marco, Genz, Kerstin, Reith, Ellen, Pospischil, Dana, Govindarajalu, Suresh, Dzietko, Mark, Pesditschek, Stefanie, Mai, Ingrid, Dikranian, Krikor, Olney, John W., Ikonomidou, Chrysanthy
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants
Anticonvulsants - therapeutic use
Apoptosis - drug effects
Apoptosis - physiology
Biological Sciences
Brain
Brain - drug effects
Brain - growth & development
Brain - pathology
Brain-Derived Neurotrophic Factor - genetics
Diazepam - therapeutic use
Disease Models, Animal
DNA Primers
Dosage
Epilepsy
Humans
Nerve Degeneration - pathology
Nerve Degeneration - physiopathology
Nerve Degeneration - prevention & control
Nerve Tissue Proteins - genetics
Neurology
Neurons
Neurotoxicity
Phenobarbital - therapeutic use
Prescription drugs
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Seizures
Thalamus
Vehicles
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.222550499