Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

TLDR

Epilepsy is the most common neurological disorder in children, with 150,000 first seizures annually in the U.S., and antiepileptic drugs used to treat it are linked to cognitive impairment, microcephaly, and birth defects, though the underlying cause remains unknown. In developing rat brains, clinically relevant doses of phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate induce apoptotic neurodegeneration associated with reduced neurotrophins, while beta‑estradiol mitigates this effect, offering a possible explanation for the cognitive deficits seen with prenatal or postnatal antiepileptic exposure.

Abstract

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. beta-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.