Summary: Rapamycin may counteract the harmful effects of Sodium Valproate, a typical seizure medicines, on maternal spinal cord development. Although calcium valproate is frequently prescribed, it can be dangerous during pregnancy, causing cervical misformations in babies.
Researchers discovered how the drug causes malformations by using organoids ( human mini-spinal cords ), and that co-treatment with Rapamycin prevents these effects by using the drug. This development may allow pregnant women who have seizure to continue taking their medications without risk.
Important Information:
- When taken while pregnant, saline vaproate can lead to spinal problems in babies.
- Scientists used organoids to investigate and stop these damaging effects.
- Pregnant women may benefit from combining Rapamycin and the seizure medicine in a safer manner.
Origin: University of Queensland
Researchers at the University of Queensland have made a major step in providing safe exposure to a common and potent anti-seizure drugs for people with epilepsy.
Sodium Valproate , or valproic acid, is frequently used to treat epilepsy and other mental illnesses, but it is thought to be dangerous to use during pregnancy because of its association with lumbar cable problems and other problems that newborns experience.
Dr Giovanni Pietrogrande , and , Professor Ernst Wolvetang , from UQ’s , Australian Institute for Bioengineering and Nanotechnology , ( AIBN ) led a team of organoid experts who have identified a drug that could nullify the dangerous side effects.  ,  ,
” We started by figuring out why valproate factors spinal cord abnormalities in fetuses,” said Dr. Pietrogrande.
” To accomplish this, we created organoids – human mini-spinal strings in a dish – that closely resemble the spinal cord of a fetus in the first month of birth.
” When these tiny cervical cords were exposed to valproate, the group discovered that the substance changes the cells that typically form the spinal rope, leading to malformations.”
The AIBN staff therefore treated the organoids with Rapamycin, a scientifically proven drug, and found it prevented the side effects of valproic acid, according to Professor Wolvetang.
” So co-treatment with , Rapamycin , could be the factor that opens secure exposure to an incredibly effective treatment for women with seizure,” Professor Wolvetang said.  ,
Professor Terence O’Brien, system director and assistant director of research at Alfred Brain, study co-author, said the results could help healthcare providers and people understand the complex issues surrounding the treatment of seizures.
It may also provide a way for women to continue taking this life-saving medication while having healthy children, according to Professor O’Brien.
The study, according to Professor Wolvetang, highlights the potential for new technologies like those derived from human stem cells to study drug cellular and molecular effects.
Organoids are a tool that, according to him, allow us to develop new treatments as well as find new ways to enhance the safety and efficacy of already existing ones.
We hope that this study will add another step in the direction of TGA’s efforts to change the Therapeutic Goods Administration’s ( TGA ) regulations to make organoids a potent tool for drug discovery and screening.
The work was conducted in partnership with AIBN colleagues , Dr Mohammad Shaker,  , Dr Julio Aguado,  , Dr Ibrahim Javed,  , Professor Tom Davis,  , Tahmina Tabassum , and , Sean Morrison, as well as collaborators from UQ’s , School of Chemical Engineering, The University of Melbourne and Vita-Salute San Raffaele University in Milan.
About this research in neuropharmacology
Author: Alex Druce
Source: University of Queensland
Contact: Alex Druce – University of Queensland
Image: The image is credited to Neuroscience News
Original Research: Open access.
Giovanni Pietrogrande et al., explains that “valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models.” Molecular Psychiatry
Abstract
Senescence and Rapamycin-induced teratogenicity in human spinal cord and animal models are sown by valproic acid-induced teratogenicity.
Although valproic acid (VPA ) is effective and widely used as an anti-seizure medication, it can be teratogenic when used during pregnancy, causing unknown side effects to brain and spinal cord development.
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 discovered that VPA promotes mesenchymal differentiation of human NCCs and causes extensive cellular senescence.
Next, we demonstrate that the clinically proven drug Rapamycin, which inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in developing zebrafish, demonstrates the therapeutic potential of this approach.
Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively, our findings reveal that cellular senescence is a key factor in the development of VPA-associated neurodevelopmental teratogenicity and provide a new pharmacological approach to prevent.
These results demonstrate the potency of drug discovery using genetically modified human stem cell-derived organoid models.
