Find the target of valproic acid: pioneering the use of a non-animal model for basic biomedical (epilepsy) research

Aims

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.

Background

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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PhD Studentship

Status:

Closed

Principal investigator

Professor Robin Williams

Institution

Royal Holloway University of London

Co-Investigator

Professor Matthew Walker

Grant reference number

NC/L001500/1

Award date:

Sep 2014 - Mar 2018

Grant amount

£90,000