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Project grant

Replacing, refining and reducing animal usage in epilepsy research using a non-sentient model

Microscope view of Dictyostelium slime mold

At a glance

Award date
January 2010 - April 2013
Grant amount
Principal investigator
Professor Robin Williams


  • Professor Matthew Walker
Royal Holloway University of London


  • Replacement
Read the abstract
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Application abstract

Epilepsy is the commonest serious neurological condition, resulting in considerable morbidity and mortality. Research into the origins and mechanisms of epilepsy has quickly advanced since seizures can be induced in animals to investigate both the mechanism of epilepsy and to identify new treatments. One epilepsy treatment, Valproic acid (VPA), is now the most widely prescribed drug worldwide, but surprisingly, its mechanism of action remains unclear. This project will follow NC3Rs criteria for research by replacing and reducing animals in developing a non-sentient model system for understanding the basis of the anti-epileptic effects of VPA and in identifying novel epilepsy treatments. This is a necessary approach, since the current analysis of one potential new epilepsy drug employs at least two experimental animal models at five drug doses with eight animals per dose - thus around 100 animals are used per compound. Dictyostelium is a non-sentient biomedical model that we have used as a replacement for animals in understanding the cellular effects of VPA. Our recent discovery of a VPA-catalysed inhibition of phosphoinositide (PI) signalling through attenuating de novo inositol biosynthesis in this model is consistent with this effect being the mechanism for seizure control. We have also shown that increased PI inhibition for VPA-related compounds correlates with increased seizure control, and have shown one novel compound strongly increased seizure-control effects in mice compared to VPA. Our data therefore suggests VPA may function in seizure control through inhibition of de novo inositol biosynthesis. This project will define the mechanism of VPA inhibited inositol attenuation. We will then follow a staged process, first identifying novel compounds showing this effect in Dictyostelium, and then analysing a limited number of drugs in animal seizure models to confirm transferability of these effects to animal systems. The project will finally test three compounds on long-term seizure control using new technology in refined experiments to develop better treatments for epilepsy. The project will therefore replace and reduce animal research by employing a simple non-sentient model to better understand the basis of epilepsy and for the development of new epilepsy treatments, and refine animal usage to prove the efficacy of these drugs. We estimate screening 40 compounds will need 100 animals, reducing animal usage in the development of these drugs by 3900. The project is highly likely to help to unravel the complex way in which VPA stops epilepsy in the human population and to develop new treatments for epilepsy.



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