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Antiepileptic drugs and apoptotic neurodegeneration in the developing brain
Petra Bittigau1, Marco Sifringer, Kerstin Genz
1Department of Pediatric Neurology, Children's Hospital, Charite-Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Insights
Common antiepileptic drugs (AEDs) cause brain cell death in developing rats. This neurodegeneration may explain cognitive issues and reduced brain mass in children exposed to these medications.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pharmacology
Background:
- Epilepsy is a common neurological disorder in children.
- Antiepileptic drugs (AEDs) are used to treat seizures in vulnerable populations, including children and pregnant women.
- AEDs can cause adverse effects like cognitive impairment and birth defects, but the underlying mechanisms are unknown.
Purpose of the Study:
- To investigate the mechanism by which AEDs cause neurodevelopmental toxicity.
- To determine if specific AEDs induce neuronal death in the developing brain.
- To explore potential therapeutic interventions for AED-induced neurotoxicity.
Main Methods:
- Administered AEDs (phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, valproate) to developing rats.
- Measured AED plasma concentrations to ensure relevance to human therapeutic levels.
- Assessed neuronal apoptosis, neurotrophin expression, and survival-promoting protein concentrations in the rat brain.
- Evaluated the effect of beta-estradiol on AED-induced neurodegeneration.
Main Results:
- Several AEDs induced apoptotic neurodegeneration in the developing rat brain at human-relevant concentrations.
- Neuronal death correlated with reduced neurotrophin expression and decreased levels of survival-promoting proteins.
- Beta-estradiol administration ameliorated AED-induced apoptotic neurodegeneration.
Conclusions:
- AEDs can cause apoptotic neurodegeneration in the developing brain, potentially explaining cognitive impairments and reduced brain mass.
- Reduced neurotrophin signaling pathways may mediate AED-induced neurotoxicity.
- Beta-estradiol shows promise as a therapeutic agent to counteract AED-induced neurodevelopmental toxicity.
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.