50 years after valproate was first discovered, research published today in the journal Neurobiology of Disease, reports how the drug works to block seizure progression.
Valproate (variously labelled worldwide as Epilim, Depacon, Depakene, Depakote, Orlept, Episenta, Orfiril, and Convulex) is one of the world's most highly prescribed treatments for epilepsy. It was first discovered to be an effective treatment for epilepsy, by accident, in 1963 by a group of French scientists.
In thousands of subsequent experiments, animals have been used to investigate how valproate blocks seizures, without success. Scientists from Royal Holloway University and University College London have now identified how valproate blocks seizures in the brain, by using a simple amoeba, Dictyostelium discoideum.
The research is funded by a project grant from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).
"The discovery of how valproate blocks seizures, initially using the social amoeba Dictyostelium, and then replicated using accepted seizure models, highlights the successful use of non-animal testing in biomedical research," said Professor Robin Williams from the School of Biological Sciences at Royal Holloway.
"Sodium valproate is one of the most effective antiepileptic drugs in many people with epilepsy, but its use has been limited by side-effects, in particular its effect in pregnant women on the unborn child," said Professor Matthew Walker from the Institute of Neurology at University College London.
"Understanding valproate's mechanism of action is a first step to developing even more effective drugs that lack many of valproate's side-effects.
"Our results also showed that the decrease of a specific chemical in the brain at the start of the seizure causes even more seizure activity. This holds important implications for identifying the underlying cause," added Professor Williams.
The authors describe that since the discovery of how valproate works in Dictyostelium - through controlling the level of an important chemical, PIP3 (phosphatidylinositol [35]-triphosphate) - this research has now led to the discovery of an effect of seizure activity to reduce PIP3 levels. Valproate has been found to work by restoring these levels to produce an anti-seizure effect. However the authors state that subsequent studies will be necessary to investigate this mechanism in other seizure models.
PIP3 contributes to cell signalling and has an important regulatory role in acute cellular physiology (such as synaptic transmission) and maintaining basal cellular activity.
Dr Vicky Robinson, Chief Executive, NC3Rs said: "This breakthrough reflects the necessity to fund original research to develop alternatives to using animals as models of human disease. The work will help to deliver genuine progress in the 3Rs for epilepsy research."
The NC3Rs-funded epilepsy research builds on work where 98% of animal use by this group has been replaced with the simple amoeba to initially screen and identify improved epilepsy treatments.
Paper reference:
Chang P, Walker MC, Williams RSB (2013). Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid. Neurobiology of Disease http://dx.doi.org/10.1016/j.nbd.2013.10.017
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