Antiepileptic drugs and apoptosis in the developing brain.
Epilepsy is the most common neurologic disorder in young humans. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects by unknown mechanisms. We tested whether common AEDs cause neurodegeneration in the developing rat brain. Rats aged 3-30 days received phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, or valproic acid. Histologic examination of the brains revealed that these drugs cause widespread and dose-dependent apoptotic neurodegeneration in the developing rat brain during the brain growth spurt period. Apoptotic neurodegeneration was triggered at plasma drug levels relevant for seizure control in humans. Antiepileptic drugs lead to reduced expression of neurotrophins and decreased concentrations of the active forms of ERK1/2, RAF, and AKT. beta-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorated AEDs-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with pre- or postnatal exposure of humans to antiepileptic therapy.
Bittigau
Petra
P
Department of Pediatric Neurology, Children's Hospital, Charite-Virchow Clinics, Humboldt University, Berlin, Germany. petra.bittigau@charite.de
Sifringer
Marco
M
Ikonomidou
Chrysanthy
C
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002648:Child; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D004958:Estradiol; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases