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1Department of Developmental Molecular Genetics, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
Insights
New antiepileptic drugs like vigabatrin can harm brain development. This study in mice shows vigabatrin exposure during early life causes lasting cognitive and motor deficits, highlighting risks for developing brains.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Antiepileptic drugs potentiating GABA-ergic pathways may negatively impact brain development.
- Previous reports indicate an increased risk of intellectual impairment in children exposed to these drugs in utero.
Purpose of the Study:
- To investigate the neurodevelopmental effects of vigabatrin, a novel antiepileptic drug.
- To assess the vulnerability of the developing mouse brain to vigabatrin during specific early postnatal periods mirroring human third-trimester development.
Main Methods:
- Newborn mice were treated with vigabatrin during two distinct periods: postnatal days 1-7 and 4-14.
- Behavioral assessments included sensory/motor reflex development, open field mobility, object recognition, and spatial learning/memory.
- Morphological analysis examined hippocampal and cerebral cortex cell density in treated and control adult mice.
Main Results:
- Vigabatrin exposure led to delayed reflexes, reduced mobility, impaired object recognition, and deficits in spatial learning and memory.
- Specific motor functions showed age-dependent susceptibility to vigabatrin.
- Morphological changes included transient hippocampal alterations and reduced M2 cerebral cortex cell density in adult mice.
Conclusions:
- Vigabatrin treatment during early development causes both short- and long-term adverse effects on brain function and structure.
- The developing motor system exhibits particular vulnerability to GABA enhancement during the first postnatal week.
Abstract:
Antiepileptic drugs acting through the potentiation of GABA-ergic pathways have harmful effects on brain development. Increased risk of impaired intellectual development was reported in children born to women treated for epilepsy during pregnancy. Here we examined the vulnerability of the developing brain to treatment with one of the new antiepileptic drugs--vigabatrin--during two time periods in newborn mice (postnatal days 1-7 and 4-14) which parallel the third trimester of human embryo brain development. Delayed development of sensory and motor reflexes, reduced mobility in the open field, impaired object recognition and deficient spatial learning and memory were observed independently of the treatment period. On the contrary, specific susceptibility to the age of exposure was detected in various motor functions. A number of morphological correlates may explain these behavioral alterations; a transient increase in CA1 pyramidal cell layer (P < 0.001) and decrease in granular cell layer (P < 0.05) in hippocampus were detected at postnatal day 7. In addition, a significantly lower cell density was observed in the adult mouse brain in all layers of the M2 cerebral cortex of mice treated during days 4-14, compared to the controls (P < 0.05). Our findings demonstrated short- and long-term deleterious effects of vigabatrin treatment and suggest a specific vulnerability of the developing motor system to GABA enhancement during the first postnatal week.
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