Pioneering zebrafish research provides breakthrough in the development of new treatments for epilepsy

The prospect of developing new treatments for epilepsy sufferers has been given a boost by a pioneering discovery at a leading international centre of research into human disease in the University of Sheffield.
Researchers at the University’s Medical Research Council Centre for Developmental and Biomedical Genetics (CDBG), in the Department of Biomedical Science, screened a collection of 2,000 biologically active compounds to identify molecules that suppressed epileptic seizures in two day old epileptic zebrafish.

Within this collection, 46 compounds – including some which are used to treat infectious, psychiatric and inflammatory disorders – were found to exhibit anticonvulsant activity and could represent starting points for the development of new drugs for treating epilepsy.

Approximately one out of every 140 people in the UK has epilepsy – more than 400,000 people – of which about 30 per cent do not respond favourably to the available anti-epileptic drugs.
Consequently, many patients live with the disruptive and often devastating effects of untreatable seizures in their daily lives, whilst other patients who receive medication for their seizures experience side-effects that can result from taking some of these drugs.

The University of Sheffield team’s innovative approach to identifying small molecules with potential as anti-epileptic therapies offers new prospects of reducing the burden of suffering from this devastating illness.

Dr Vincent Cunliffe of the University of Sheffield’s Department of Biomedical Science, who led the project, said: “We took advantage of a unique set of features of the zebrafish to look for new anticonvulsant agents within a library of many different types of compounds with a wide range of known biological activities.
“We found that a small number of them had previously-unknown anti-convulsant effects. Some of the identified compounds already have a variety of different medical uses in treating conditions such as fungal infections, as well as psychiatric and inflammatory disorders.”

The research, published in the journal Disease Models & Mechanisms, suggests that some of these existing drugs could be re-purposed for treatment of epilepsy.
Nerve cells communicate with one another by passing electrical impulses along their lengths, leading to the release of a variety of chemical signals known as neurotransmitters at nerve endings, which may then stimulate or inhibit neighboring cells.

Epileptic seizures occur as a result of imbalances in the types of neurotransmitters produced within the brain, causing the simultaneous activation of abnormally large numbers of nerve cells, some of which may then stimulate body muscles to contract vigorously, resulting in convulsions.
Observing these processes at the level of individual nerve cells and molecules is especially difficult because the brains of mammals such as humans and mice, are so large, complex and relatively inaccessible.

However, the three milimetre-long, microscopic zebrafish larva develops rapidly, independently of its parents, and it is structurally simple, transparent and accessible, which allows the behaviours of nerve cells within the brain to be easily viewed in a remarkable level of detail. To study the effects of drugs on the zebrafish brain, they are simply diluted into the water in which the zebrafish develop, which then allows them to be readily absorbed by the body.

Dr Cunliffe added: “The zebrafish is proving to be a remarkably powerful in vivo system for gene function analysis and drug discovery. Over the last ten years our zebrafish research has helped us to understand how the nervous system is built and how faults in this construction process may cause neurological and psychiatric diseases.

“Three years ago we began to explore the usefulness of the zebrafish for drug discovery and we have been surprised by the success we have had in a relatively short period of time.”
More traditional approaches to identifying and developing new pharmaceuticals are slower and more costly, so adopting the zebrafish – a small tropical fish of the minnow family – for this type of research, could help to shorten the timescales and reduce the overall costs of drug development.

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