ANTIEPILEPTIC DRUGS AND APOPTOSIS IN DEVELOPING BRAIN

Epilepsy is the most common neurological disorder of young age in humans. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters and second messenger systems constitute molecular targets of AEDs. These same targets regulate brain processes which are critical for propagation of seizures but also essential for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain development in undesired ways.

Recent research has shown that major AEDs can disturb the process of physiological apoptosis in the developing rodent brain. Barbiturates, benzodiazepines, valproate, phenytoin, vigabatrin and sulthiame may cause apoptotic neurodegeneration in the developing rat brain at doses and plasma concentrations relevant for seizure control. This neurotoxic effect is limited to a developmental period characterized by rapid brain growth and active synaptogenesis, which in the human starts in the third trimester of gestation and extends to the third year of life. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. 17β-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AEDs-induced apoptotic neurodegeneration.

These findings point towards one possible mechanism that can explain cognitive impairment and reduced brain mass associated with pre- or postnatal exposure of humans to antiepileptic therapy.