French researchers are taking a new step to understand the impact of valproic acid on the development of the nervous system. Taken during pregnancy, this antiepileptic can cause developmental problems in the baby.
Between 17,000 and 30,000 children in France have cognitive impairments or autism spectrum disorders following in utero exposure to valproic acid (VPA). This medicine is notably prescribed to treat epilepsy, migraine or even bipolar disorders. In 2018, the European Medicine Agency had however recommended that it no longer be offered to pregnant women, aware that they ran a considerably increased risk of giving birth to children with developmental defects. Some babies also develop birth defects such as microcephaly (an abnormally small head) or spina bifida. How does VPA cause these abnormalities at the cellular and molecular level? French researchers* have looked into the matter. Their work is published in June 2022 in the scientific journal Plos Biology (study in English in link below).
Stopping cell development
After studying mouse embryos, scientists discovered that valproic acid activated a process of brain cell senescence. ” Senescence is the irreversible arrest of the cell cycle, which results in cell death. “, they specify, and is at the origin of the aging of organisms. Initiated at the wrong time, at an embryonic stage, it can therefore cause cognitive or neural development disorders (i.e. relating to the nervous system). They then observed similar results in human neuroepithelial (central nervous system) cells.
Identification of a key protein
To go further and better understand how this process of deleterious senescence takes place, the researchers conducted genetic studies on mice and thus showed the involvement of a protein called p19Arf. They also demonstrated that the triggering of this senescence in neuroepithelial cells, under the control of p19Arf, is associated with defects in the development of the nervous system and microcephaly but not with other abnormalities, such as spina bifida, which are sometimes caused by the drug. The team now wants to continue studying senescence in other models to understand the role of this process in various developmental disorders. ” Further studies will deepen our work to identify other mechanisms involved. “, concludes Bill Keyes, Inserm researcher, last author of the study.
The antiepileptics implicated
The battle once morest sodium valproate (another name for valproic acid) began with the Depakine scandal, this antiepileptic drug responsible for mental disorders in approximately 30,000 children as well as other disabilities (linked articles below). below). In May 2022, the French pharmaceutical group Sanofi was also ordered by the Nanterre court to compensate up to 450,000 euros to a family whose daughter, exposed in utero, was born in 2005 with malformations. The lab as well as the State (via the ANSM which, at the time, in 2020, is under investigation) are accused of having delayed in informing regarding the risks of the drug for pregnant women. Other families of severely disabled children have also won their case… Finally, according to a press release from the National Medicines Safety Agency (ANSM) in July 2022, another antiepileptic, topiramate would multiply by three the risk of autism or intellectual disability in the unborn child (article in link below). It also promotes the risk of malformations (hare lip, poor placement of the urethra on the penis) as well as a very low birth weight.
* from Inserm, CNRS (National Center for Scientific Research) and the University of Strasbourg at the Institute of Genetics and Molecular and Cellular Biology (IGBMC)
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