Replacing, Refining, and Reducing Animal Usage in Epilepsy Research Using a Non-Sentient Model
Lead Research Organisation:
Royal Holloway University of London
Department Name: Biological Sciences
Abstract
Epilepsy is a chronic medical condition, whereby patients experience often debilitating seizures, greatly affecting their quality of life. At least 40 million people worldwide (6 million people in Europe) have epilepsy. It has a tremendous impact not only to the individual but also to society - the estimated total cost of epilepsy in Europe in 2004 was ?15.5 billion. Current scientific research into epilepsy almost exclusively employs laboratory animals. These animal experiments, primarily in mice, lead to the accidental discovery of Epilim in 1963 as an effective drug in seizure control, and Epilim is now the most widely prescribed drug for epilepsy treatment worldwide. Surprisingly, how the drug works in controlling seizures is unclear, and this has blocked scientists from developing more effective treatments or treatments with reduced side effects. Currently, thousands of mice are killed annually for epilepsy-based experiments.
We have recently tested a simple, single celled organism (an amoeba, Dictyostelium) for use in replacing animals in epilepsy research. In these studies, we have identified a novel effect of Epilim in regulating a critical process in how cells signal - by reducing the processing of a family of chemical within cells. These chemicals are known to control a number of cellular functions that are over-activated in epilepsy, thus this effect is likely to be involved in epilepsy control. We have also confirmed that these experiments are related to epilepsy control since we have tested one drug identified in Dictyostelium in mice and show the novel drug has better seizure control effects than Epilim.
The project outlined here will thus develop Dictyostelium as a model for epilepsy research. The model will be used to identify new epilepsy treatments and to understand the basis for the drug action, and then test a small number of lead compounds in animal models. Final compounds will be tested in refined chronic seizure models. This project will therefore develop a simple model to replace and reduce and mice in epilepsy research, and refine experiments on long-term seizure control. We estimate that in this project, 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 Epilim stops epilepsy in the human population and to develop new treatments for epilepsy.
We have recently tested a simple, single celled organism (an amoeba, Dictyostelium) for use in replacing animals in epilepsy research. In these studies, we have identified a novel effect of Epilim in regulating a critical process in how cells signal - by reducing the processing of a family of chemical within cells. These chemicals are known to control a number of cellular functions that are over-activated in epilepsy, thus this effect is likely to be involved in epilepsy control. We have also confirmed that these experiments are related to epilepsy control since we have tested one drug identified in Dictyostelium in mice and show the novel drug has better seizure control effects than Epilim.
The project outlined here will thus develop Dictyostelium as a model for epilepsy research. The model will be used to identify new epilepsy treatments and to understand the basis for the drug action, and then test a small number of lead compounds in animal models. Final compounds will be tested in refined chronic seizure models. This project will therefore develop a simple model to replace and reduce and mice in epilepsy research, and refine experiments on long-term seizure control. We estimate that in this project, 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 Epilim stops epilepsy in the human population and to develop new treatments for epilepsy.
Technical Summary
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 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.
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 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.
