Drug-resistant epilepsy has remained a problem since the inception of antiepileptic drug development, despite the large variety of antiepileptic drugs available today. Moreover, the mechanism-of-action of these drugs is often unknown. This is due to the widespread screening of compounds through animal models. We have taken a different approach to antiepileptic drug discovery and have identified a biochemical pathway in Dictyostelium discoideum (a ‘slime mould’) that may relate to the mechanism-of-action of valproate, one of the most commonly used and effective antiepileptic drugs. Through screening in this pathway, we have been able to identify a whole host of fatty acids and fatty acid derivatives with potential antiepileptic activity; this was then confirmed in in vitro and in vivo mammalian seizure models. Some of these compounds are more potent than valproate and potentially lack many of the major side effects of valproate (including birth defects and liver toxicity). In addition, one of the compounds that we have identified is a major constituent of the ketogenic diet, strongly arguing that it may be the fatty acids and not the ketogenesis that are mediating the effect of this diet.

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