title: New experimental therapies for status epilepticus in preclinical development.
abstract: Starting with the established antiepileptic drug, valproic acid, we have taken a novel approach to develop new antiseizure drugs that may be effective in status epilepticus. We first identified that valproic acid has a potent effect on a biochemical pathway, the phosphoinositide pathway, in Dictyostelium discoideum, and we demonstrated that this may relate to its mechanism of action against seizures in mammalian systems. Through screening in this pathway, we have identified a large array of fatty acids and fatty acid derivatives with antiseizure potential. These were then evaluated in an in vitro mammalian system. One compound that we identified through this process is a major constituent of the ketogenic diet, strongly arguing that it may be the fatty acids that are mediating the antiseizure effect of this diet. We further tested two of the more potent compounds in an in vivo model of status epilepticus and demonstrated that they were more effective than valproic acid in treating the status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus".
authors.affiliation: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, WC1N 3BG, UK. Electronic address: m.walker@ucl.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK. Electronic address: robin.williams@rhul.ac.uk.
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004023:Dictyostelium / Q000187:drug effects / Q000378:metabolism; D055423:Diet, Ketogenic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D010716:Phosphatidylinositols / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000178:diet therapy / Q000188:drug therapy / Q000628:therapy*; D035703:Therapies, Investigational; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D010716:Phosphatidylinositols; D014635:Valproic Acid
keywords: Decanoic acid; Dictyostelium; Ketogenic diet; Seizure models; Status epilepticus; Valproic acid