Sodium valproate is a commonly used medication to treat epilepsy, but its use during pregnancy can be risky, as it has been linked to an increased risk of birth defects, such as spinal defects in the baby. Recent research has found that another medication, rapamycin, may counteract these adverse effects. This breakthrough brings hope to women with epilepsy, as it may allow them to continue their treatment more safely during pregnancy, avoiding risks to the developing baby.
Epilepsy, also known as a seizure disorder, is a brain condition that causes recurring seizures. There are many types of epilepsy. In some people, the cause can be identified. In others, the cause is unknown. Epilepsy is common, and an estimated 1.2 percent of people in the United States have active epilepsy, according to the Centers for Disease Control and Prevention. Epilepsy affects people of all genders, races, ethnicities, and ages.
Seizure symptoms can vary widely. Some people may lose consciousness during a seizure, while others may not. Some people stare blankly for a few seconds during a seizure. Others may repeatedly jerk their arms or legs, movements known as convulsions. Having a single seizure does not mean you have epilepsy.
Epilepsy is diagnosed if you have had at least two unprovoked seizures at least 24 hours apart. Unprovoked seizures do not have a clear cause.
Treatment with medication or sometimes surgery can control seizures for most people with epilepsy. Some people require lifelong treatment. This is why it is a problem for women who want to get pregnant and is even contraindicated.
Valproic acid (VPA) is a widely used medication to treat epilepsy, bipolar disorder, and migraines. However, its use during pregnancy is risky, as it can cause many birth defects, including heart problems, craniofacial defects, and neural tube defects (which involve the formation of the brain and spinal cord).
These problems are known as Fetal Valproate Syndrome (FVS). Because of these risks, VPA is contraindicated in pregnant women, and, in many countries, its prescription for women of childbearing age is discouraged.
Unfortunately, some women with epilepsy do not have alternative treatment options that are as effective as VPA. Research in several animal models, such as zebrafish and mice, has shown that VPA causes problems in the development of neural crest cells (NCCs), which are essential for the formation of many tissues in the embryo, including cells of the nervous system and muscles.
To elucidate the mechanism of VPA-induced teratogenicity, scientists at the University of Queensland developed a special technique to observe a specific type of cell (neural crest cells) during development. They used human stem cells, which have the ability to transform into several types of cells.
"Genetic recombinase" is like a molecular tool that allows specific genes to be turned on or off, and "SOX10" is a genetic marker that identifies these neural crest cells.
Using this system, scientists were able to observe the behavior of these cells in a laboratory model that mimics the development of the human nervous system (using organoids, which are like "mini-organs" grown in the laboratory). This helped them understand how these cells move and develop.
They discovered that valproic acid (VPA), a drug, causes these cells to stop dividing (a process called cellular senescence) and start transforming into another type of cell (mesenchymal cells), which should not appear at this stage of development.
Example of human brain organoids growing in culture for 6 months
The good news is that scientists have found that rapamycin, a drug already approved for clinical use, was able to “correct” these detrimental effects of VPA, preventing the cells from behaving abnormally. They found that a molecule called AP1 is one of the drivers of these changes in the cells, indicating a specific target that may be important in controlling these effects.
This shows how these laboratory models (organoids) are powerful tools for testing new drugs and better understanding how substances affect the human body.
The next step was to test the same theory in a living organism. Remarkably, the in vivo zebrafish model replicates the VPA-induced NCC differentiation defects and subsequent Rapamycin rescue, providing further validation of the biological significance of these findings beyond the in vitro setting.
Rapamycin prevents VPA-induced promotion of NCC differentiation in zebrafish. a) Representative image of zebrafish larvae and zoom of the cranial region at 48 hours exposed to the compounds. b) Representative brightfield images overlaid with confocal images of zebrafish larvae exposed to multiple compounds and immunostained for Sox10 (green) and 3D reconstruction of Sox10+ cells identified within the larvae. c) Quantification of the number of Sox10-positive cells counted in the palate region (purple), d) head and entire upper body of zebrafish larvae exposed to vehicle, VPA, and VPA+Rapamycin. https://doi.org/10.1038/s41380-024-02732-0
Finally, the researchers identified the master transcription factor AP1 as a likely mediator of VPA-induced senescence and aberrant differentiation. Collectively, these data shed light on the delicate balance between cellular senescence and cell fate choices that underlie VPA teratogenicity and identify a potential pharmacological prevention strategy through Rapamycin treatment.
This discovery may pave the way for women who depend on VPA to take the drug more safely during pregnancy in the future, reducing the risk of harm to the fetus.
This advance is promising because it highlights the potential of using sophisticated laboratory models to find new ways to treat and prevent pregnancy complications, especially for those who must continue taking anticonvulsants.
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Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models.
Pietrogrande, G., Shaker, M.R., Stednitz, S.J. et al.
Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02732-0
Abstract:
Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.
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