Abstract
Human studies of neurodevelopment suggest that children exposed in utero to certain antiepileptic drugs (AEDs) suffer a variety of brain-behavior sequelae, such as neural tube defects, developmental delays, cognitive deficits, etc. Valproic acid (VPA), a commonly used AED, has greater risk for these side effects compared with other AEDs. However, the detailed molecular mechanisms underlying this developmental neurotoxicity of VPA is unclear despite previous research demonstrating that VPA could induce widespread apoptotic neurodegeneration in developing brains of animal models. This study characterizes the role of astrocytes in VPA-induced neurodegeneration. In developing brains, we evaluated the developmental neurotoxicity of VPA on differentiating neurons and astrocytes from neural progenitor cells cultured from the hippocampus of human fetuses. Exposure of a neuron-enriched culture to VPA at 250μM or 500μM did not cause neuronal apoptosis, but at 1mM and 7 days exposure, a slight increase in the percentage of apoptotic cells was observed. In contrast, VPA at 250μM to 1mM, selectively induced neuronal apoptosis in a neuron-astrocyte mixed cell culture model. The VPA-treated astrocytes showed morphological changes, and the lev...Continue Reading
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