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Developmental biology - Birth Defects|
Antiepileptic drug induces birth defects
A common drug widely-used for treating epileptic seizures — AED valproic acid — can lead to birth defects. If used in early pregnancy, it interfers with glutamate signals in neural tube formation, according to a study by UC Davis School of Medicine and published in the Journal of Neuroscience.
Conducted with frogs, the study could begin development of new epilepsy medications safer for pregnant women.
"Neural tube defects such as spina bifida are among the most common birth defects. In serious cases, they can lead to neurological deficits and even infant death. The brain and spinal cord begin as a group of cells in the embryo that folds in on itself to form the neural tube. Some of the most common birth defects are caused by a neural tube that fails to close completely. The side effects of antiepileptic drugs (AEDs) are thought to contribute to the prevalence of birth defects among children of epileptic mothers, but the mechanisms involved are not known."
Current theories have focused on side effects of epileptic drugs, but not on their primary targets. The prevailing view had been that in early stages of nervous system development neural activity was neither apparent nor relevant.
Borodinsky challenged that view and demonstrates how glutamate signaling in clawed frogs is present and needed in neural tube formation.
"The brain and spinal cord begin as a group of cells in the embryo that folds in on itself to form the neural tube. Some of the most common birth defects are caused by a neural tube that fails to close completely. Side effects of antiepileptic drugs (AEDs) are thought to contribute to the prevalence of birth defects among children of epileptic mothers, but the mechanisms involved were not known..."
Using multiple experimental approaches, the UC Davis team showed that the neurotransmitter glutamate and N-methyl-aspartate (NMDA) receptors play an important part in the proliferation and migration of the cells that form the neural tube — but are compromised in embryos treated with the widely-used AED valproic acid leading to defects.
Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that N-methyl-D-aspartate (NMDA) receptors are important for the formation of the neural tube and loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.
Neural tube defects are one of the most common birth defects. Clinical investigations have determined that use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that are the side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.
Authors: Eduardo B. Sequerra, Raman Goyal, Patricio A. Castro, Jacqueline B. Levin and Laura N. Borodinsky.
Authors report having no personal financial interests related to the study.
This study was funded by the Wellcome and the Medical Research Council, and core funding to the Gurdon Institute from the Wellcome and Cancer Research UK.
Thanks go to Drs. Nicholas Spitzer and Andrew Hamilton for comments on the manuscript. This work was supported by the Basil O'Connor Starter Scholar Research Award Grant 5-FY09-131 from the March of Dimes Foundation, Klingenstein Foundation Award in Neuroscience, NSF 1120796, NIH-NINDS R01NS073055 and Shriners Hospital for Children 86500-NCA, 85220-NCA, 85300-NCA grants to LNB and by the Epilepsy Foundation and Shriners Hospital for Children postdoctoral fellowships to EBS.
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Neural tube formation was compromised in frog embryos treated with the widely-used antiepileptic drug Valproic Acid, creating neural tube defects. Image Credit: Sequerra et al., Journal of NeuroScience