Researchers determined that valproic acid prevents nervous system cells from properly developing and dividing
When used during pregnancy, the drug valproic acid, which is used to treat bipolar disorder, migraines, and epilepsy, can lead to birth defects. Now, research recently published in the journal PLoS Biology by Bill Keyes of the Institute of Genetics and Molecular and Cellular Biology, France, and associates gives one explanation for why: Valproic acid (VPA) causes certain nervous system development cells to enter a condition known as senescence, which prevents them from properly growing and dividing.
VPA is frequently used to treat a variety of diseases. However, since its first use, there have been many instances of pregnant women using VPA giving birth to kids who had birth abnormalities such as spina bifida, facial changes, and heart malformations. A third of exposed newborns also develop cognitive decline and Autism Spectrum Disorder.
Keyes and colleagues examined embryonic exposure to VPA in the new study by using both human organoids—three-dimensional collections of human cells generated in the lab—and mice. They found that neuroepithelial cells, which are the stem cells that give rise to the central nervous system, undergo cellular senescence as a result of VPA. The researchers also identified p19Arf as the specific molecule that caused this VPA-induced senescence. Although VPA exposure during pregnancy still resulted in other abnormalities, the scientists found that it no longer produced microcephaly (a small head size) or alterations to gene expression patterns linked to autism spectrum disorder in mice missing the p19Arf gene.
Valproic acid is used to treat the manic phase of bipolar disorder, seizures, and migraine headaches. This prescription medication goes by various brand names including Depakene, Depakote, Depakote DR, Depakote ER, Depakote Sprinkles, Stavzor, and Alti-Valproic.
The work is one of the first to associate cellular senescence with developmental defects, the authors say. “Overall, the discovery that atypical activation of senescence in the embryo can perturb development raises the intriguing possibility that it may also contribute to defects in developmental contexts beyond those we studied here.”
Muriel Rhinn, the first author of the study, adds, “While cellular senescence has long been associated with aging and age-related disease, we now show that aberrant induction of senescence can also contribute to developmental defects. As valproic acid is strongly linked to cognitive defects and Autism Spectrum Disorder, this study now introduces an exciting link with senescence, supporting how additional studies are needed.”
This study was funded by grants from La Fondation pour la Recherche Medicale (FRM) (AJE20160635985), Fondation ARC pour la Recherche sur le Cancer (PJA20181208104), IDEX Attractivité – University of Strasbourg (IDEX2017), La Fondation Schlumberger pour l’Education et la Recherche FSER 19 (Year 2018)/FRM, Agence Nationale de la Recherche (ANR) (ANR-19-CE13-0023-03) and Ligue Contre le Cancer (all to W.M.K.). I.Z.B. was supported by a 4th-year fellowship from the Fondation ARC pour la Recherche sur le Cancer and a Ph.D. fellowship from INSERM and Conseil Regional Grand-Est. A.K. was supported by a fellowship from Eur IMCBiO. The work was also supported by an institutional grant to the IGBMC, ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. Sequencing was performed by the GenomEast platform, a member of the “France Génomique” consortium (ANR-10-INBS-0009). The funders had no role in the study’s design, data collection, and analysis, decision to publish, or preparation of the manuscript.
Reference: “Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects” by Muriel Rhinn, Irene Zapata-Bodalo, Annabelle Klein, Jean-Luc Plassat, Tania Knauer-Meyer and William M. Keyes, 14 June 2022, PLoS Biology.