Professor Robin Williams, from Royal Holloway University of London, has used an NC3Rs project grant awarded in 2009 to develop a Dictyostelium model for the screening of compounds for seizure control.
Principal Investigator: Robin Williams, Professor of Molecular Cell Biology
Organisation: Royal Holloway, University of London
Award: £415,248, in 2009, over 36 months
Title: Replacing, refining and reducing animal usage in epilepsy research using a non-sentient model
Read more about Professor Williams' research
Around 50 million people worldwide have epilepsy
Epilepsy is a chronic neurological condition characterised by repeated seizures. Around 50 million people worldwide have epilepsy. Anti-epileptic drugs are the mainstay of treatment but current therapies are poorly effective in around one third of people (approximately 160,000 people in the UK alone).
Epilepsy research is currently dependent on the use of animals
Investigating the changes that occur in neural activity in the brain during an epileptic seizure almost exclusively uses animals, either as a source of primary cells or brain slices for in vitro experiments or for in vivo studies. Worldwide an estimated 500,000 rodents are used annually for epilepsy research. Some of the procedures can be distressing for the animals involved and in the UK they are classified as causing moderate or severe suffering.
Studies, mainly in mice and rats, led in 1963 to the accidental discovery that the short-chain fatty acid sodium valproate is an effective drug in seizure control. Today, sodium valporate is globally the most widely prescribed drug for epilepsy treatment, accounting for 52% of prescriptions. It is, however, associated with a number of side effects, including hepatoxicity and teratogenicity. Work to provide improved treatments with fewer side effects have been hampered by a lack of understanding of the mechanism of action of sodium valproate.
Using amoebae to identify potential anti-epileptic drugs
In 2009, Professor Robin Williams, Royal Holloway, University of London, was awarded NC3Rs funding to develop Dictyostelium discoideum as a model system for studying the molecular pharmacology of sodium valproate, providing a basis for discovering potentially new anti-epileptic drugs.
Dictyostelium discoideum is a social amoeba found in forests. It can easily be grown in the laboratory and is commonly used for studies on cell movement and signalling. At times of starvation, the amoeba aggregate to form multicellular fruiting bodies. Professor Williams has demonstrated that sodium valproate inhibits chemotactic cell movement in Dictyostelium by attenuating phosphoinositide turnover.
Using this biochemical pathway, a wide range of compounds that are chemically similar to sodium valproate have been screened in the Dictyostelium model system. This has identified new fatty acids and fatty acid derivatives with potential anti-epileptic activity. Working with Professor Matthew Walker, Head of the Department of Clinical and Experimental Epilepsy, University College London, the fatty acids have been subsequently tested in rat ex vivo hippocampal slice models of seizure-like activity and in vitro hepatotoxicity and teratogenicity assays. The most potent were then investigated for efficacy in vivo in a rat model of epilepsy.
Anti-epileptic drugs are typically tested for efficacy in two animal models at five doses and with around eight animals per dose. By using Dictyostelium as a pre-screen Professors Williams and Walker used 100 rats to test 60 compounds; the standard approach would have used 4,800 animals. This represents a 98% reduction.
A potentially improved diet to treat drug resistant epilepsy
In children with severe drug resistant epilepsy a ketogenic diet is often prescribed. Initially introduced in the 1920’s, it is essentially a ‘semi-starvation’ diet which involves heavily limited carbohydrates and lots of proteins. The diet was improved in the 1990’s to include medium-chain triglyceride (MCT) oil and to allow some carbohydrate consumption. One of the most potent anti-epileptics found in Professor Williams’ study was decanoic acid, which is a major constituent of MCT oil. This provides a mechanistic basis for how the diet works and opens the door to making a more palatable and improved diet for the control of epilepsy. A licence agreement has been signed with Nestlé’s Health Science company, Vitaflo.
There have been nine papers arising from this grant.
This case study was published in a review of our research portfolio in November 2013.