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Antiepileptic Drugs and Apoptosis in the Developing Brain
Author(s) -
BITTIGAU PETRA,
SIFRINGER MARCO,
IKONOMIDOU CHRYSANTHY
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb07517.x
Subject(s) - neurodegeneration , vigabatrin , medicine , epilepsy , clonazepam , phenobarbital , phenytoin , valproic acid , carbamazepine , pharmacology , neuroscience , anticonvulsant , psychology , disease , psychiatry
A bstract : 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. β‐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.