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.

Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. We hypothesized that two caspase‐1–processed cytokines, interleukin (IL)–1β and IL‐18, are involved in oxygen‐induced neuronal cell death. Six‐day‐old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, and 48 hours). Neuronal cell death in the brain, as assessed by Fluoro‐Jade B and silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA and protein levels of caspase 1, IL‐1β, IL‐18, and IL‐18 receptor α (IL‐18Rα). Intraperitoneal injection of recombinant human IL‐18–binding protein, a specific inhibitor of IL‐18, attenuated hyperoxic brain injury. Mice deficient in IL‐1 receptor–associated kinase 4 (IRAK‐4), which is pivotal for both IL‐1β and IL‐18 signal transduction, were protected against oxygen‐mediated neurotoxicity. These findings causally link IL‐1β and IL‐18 to hyperoxia‐induced cell death in the immature brain. These cytokines might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain, which is exquisitely sensitive to a variety of iatrogenic measures including oxygen. Ann Neurol 2005;57:50–59