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Antiepileptic drugs and apoptotic neurodegeneration in the developing brain
Open accessAbstract
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.
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Cited by
Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism
Christensen, J., Grønborg, T. K., Sørensen, M. J., Schendel, D., Parner, E. T., Pedersen, L. H., & Vestergaard, M. (2013) · JAMA · doi:10.1001/jama.2013.2270 · Cited by 1,357
Trophic actions of GABA on neuronal development
Represa, A., & Ben-Ari, Y. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.03.010 · Cited by 455
Developmental timing and critical windows for the treatment of psychiatric disorders
Marín, O. (2016) · Nature Medicine · doi:10.1038/nm.4225 · Cited by 374
Isoflurane‐induced apoptosis of oligodendrocytes in the neonatal primate brain
Brambrink, A. M., Back, S. A., Riddle, A., Gong, X., Moravec, M. D., Dissen, G. A., Creeley, C. E., Dikranian, K. T., & Olney, J. W. (2012) · Annals of Neurology · doi:10.1002/ana.23652 · Cited by 264
Self-citationChild development following in utero exposure: Levetiracetam vs sodium valproate
Shallcross, R., Bromley, R. L., Irwin, B., Bonnett, L. J., Morrow, J., & Baker, G. A. (2011) · Neurology · doi:10.1212/wnl.0b013e3182088297 · Cited by 161
Metadata
- Authors
- Bittigau, P., Sifringer, M., Genz, K., Reith, E., Pospischil, D., Govindarajalu, S., Dzietko, M., Pesditschek, S., Mai, I., Dikranian, K., Olney, J. W., & Ikonomidou, C.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2002-11-04
- Volume
- 99
- Issue
- 23
- Pages
- 15089-15094
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1994842806
- Cited by
- 779
- References
- 2
- FWCI
- 18.24
- Type
- journal article
- Language
- en
- Open access
- green
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- Bittigau, P., Sifringer, M., Genz, K., Reith, E., Pospischil, D., Govindarajalu, S., Dzietko, M., Pesditschek, S., Mai, I., Dikranian, K., Olney, J. W., & Ikonomidou, C. (2002). Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.222550499
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