Scientists have used three-dimensional brain tissue models to reveal how the widely prescribed epilepsy drug valproate disrupts critical developmental processes.
Researchers in Germany have used lab-grown models of the human brain to better understand how the epilepsy drug valproate may interfere with early brain development, providing scientists with new data on the risks associated with its use during pregnancy.
Epilepsy affects around 40 million people worldwide and valproate remains a widely used treatment for seizures as well as bipolar disorder. However, the medication is already known to increase the risk of neurodevelopmental disorders in unborn children, including autism spectrum disorders. Strict warnings are therefore in place for women of childbearing age who take the drug.
Despite years of clinical use, scientists have not fully understood how valproate disrupts the processes involved in the formation of the developing brain.
Lab-grown brain models used in study
The new study was carried out by researchers from the Karlsruhe Institute of Technology (KIT), the Heidelberg Academies of Sciences and Humanities, the University of Tübingen and Heidelberg University as part of the 3D Matter Made to Order Cluster of Excellence.
Scientists used cerebral organoids to mimic different stages of prenatal brain development and allow researchers to study neurological processes in controlled laboratory conditions.
The organoids were exposed to valproate for 30 days to simulate continuous exposure during the earliest stages of development. Researchers then examined the effects of the drug at tissue, cellular and molecular levels.
The organoids were exposed to valproate for 30 days to simulate continuous exposure during the earliest stages of development
According to the findings, valproate significantly reduced cell proliferation, disrupted the organised structure of key developmental regions and impaired the transformation of progenitor cells into mature neurons.
The study also identified major changes to the extracellular matrix, the network of molecules that provides structural and biochemical support to cells. Researchers found that exposure to valproate increased tissue stiffness, altered structural organisation and interfered with communication and signalling processes between cells. All processes that are considered essential for normal brain development.
Researchers seek better understanding of risks
“We used lab-grown models of the human brain to investigate for the first time how the drug alters the extracellular matrix and how those alterations in turn affect processes within individual cells,” said Zeynep Yentür, a research assistant in Professor Simone Mayer’s working group at KIT’s Zoological Institute.
Researchers said the findings could help improve understanding of how the drug works and potentially support future efforts to reduce risks to foetuses while preserving treatment options for patients who rely on the medication.
Despite the concerns surrounding valproate, doctors say it remains the only effective treatment for some women with epilepsy.
Researchers said the findings could help improve understanding of how the drug works and potentially support future efforts to reduce risks to foetuses
“With our research, we want to contribute to a better understanding of how the medication actually works to identify new avenues of research for mitigating the risk to foetuses,” said Yentür.
The researchers stressed that the study was conducted using laboratory tissue models and cannot replace clinical data from patients. However, they believe the work offers valuable insight into the biological mechanisms involved in early brain development.
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