This project aims to build on previous NC3Rs-funded research to demonstrate the utility of an amoeba-based model to identify how valproic acid regulates PIP3 as a possible mechanism for its antiepileptic action.
It has recently been shown with NC3Rs funding that a commonly used antiepileptic drug, valproic acid, blocks the turnover of phosphoinositides in a simple model organism, the amoeba Dictyostelium. It was subsequently demonstrated in the rat that seizures reduce hippocampal phosphatidylinositol trisphosphate (PIP3) and that this can be restored by valproic acid suggesting that the antiepileptic action of this drug may be exerted via PIP3 signalling. Many mechanisms for the activity of valproic acid have been proposed but an involvement in phosphoinositide signalling could explain a number of these. However, the detailed target of this effect is not known and while mechanistic studies in rats would require large numbers of animals the availability of the Dictyostelium model provides a viable alternative.
Research details and methods
This project will develop sensitive methods to analyse the effects of valproic acid on phosphoinositide turnover, and identify the specific enzyme targeted by valproic acid through use of gene knockouts and mutations. The project will expand the use of Dictyostelium as a model for study of phosphoinositides and epilepsy by heterologous expression of human proteins from this pathway.
Kelly E et al. (2018). Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum. Disease Models & Mechanisms 11(9) doi: 10.1242/dmm.035600
Otto GP et al. (2016). Employing Dictyostelium as an Advantageous 3Rs Model for Pharmacogenetic Research. In: Jin T., Hereld D. (eds) Chemotaxis. Methods in Molecular Biology, vol 1407. Humana Press, New York, NY doi: 10.1007/978-1-4939-3480-5_9
Otto GP et al. (2016). Non-Catalytic Roles of Presenilin Throughout Evolution. Journal of Alzheimer's disease 128:54-62. doi: 10.3233/JAD-150940
Williams RSB and Bate C (2018). Valproic acid and its congener propylisopropylacetic acid reduced the amount of soluble amyloid-β oligomers released from 7PA2 cells. Neuropharmacology 128:54-62. doi: 10.1016/j.neuropharm.2017.09.031
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- Further Funding: NC3Rs Strategic Grant, Developing a non-animal model system to investigate bitter tastants as new treatments for asthma, January 2015, £98,894
- Further Funding: NC3Rs Project Grant, Replacing, refining and reducing animal usage in epilepsy research using a non-sentient model, January 2010, £415,373