{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:21:11Z","timestamp":1790889671678,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,11,12]]},"abstract":"<jats:p>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. \u03b2-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.<\/jats:p>","DOI":"10.1073\/pnas.222550499","type":"journal-article","created":{"date-parts":[[2002,11,12]],"date-time":"2002-11-12T13:44:20Z","timestamp":1037108660000},"page":"15089-15094","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":666,"title":["Antiepileptic drugs and apoptotic neurodegeneration in the developing brain"],"prefix":"10.1073","volume":"99","author":[{"given":"Petra","family":"Bittigau","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sifringer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Genz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Reith","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Pospischil","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Govindarajalu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; 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Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Clinical Pharmacology, Humboldt University, Schumannstrasse 20\/21, 10117 Berlin, Germany; and Department of Psychiatry, Washington University School of Medicine, 4940 Children\u2032s Place, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krikor","family":"Dikranian","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Children\u2032s Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; 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