AbstractDrug-resistant epilepsy represents an important unmet medical need. Consequently, preclinical strategies have to be revisited to deliver more effective antiseizure drugs (ASDs). In the present work, several novel experimental approaches applicable to thediscovery of future ASDs were evaluated. We first compared the biochemical and electrophysiological endpoints after allylglycineinduced seizures in mice and zebrafish. The anticonvulsant efficacy and potency of five clinically used ASDs were compared in both species. Having demonstrated strong cross-species similarities in response to ASDs, we propose the use of zebrafish for highthroughputscreening aiming to discover novel, more effective compounds. In the second experimental part, we report the development and pharmacological validation of the 6 Hertz (6 Hz) corneal kindling model in mice. Repeated electrical stimulations (kindling) led to a progressive sensitization and the development of generalized motor seizures. Several ASDs were the compared between the 6 Hz and the conventional 50 Hz kindling models, revealing limited efficacy of drugs to protect against seizures in the 6 Hz paradigm. The influence of experimental conditions such as mouse strain and stimulation device on the response to ASDs was also assessed using acute 6 Hz corneal stimulation. The obtained results indicate that the genetic background of experimental animals is an important determinant of drug response, which may reflect resistance of human epilepsy to current ASDs. Finally, we studied the impact of a first inciting event (pilocarpine-induced status epilepticus) on the potency and efficacy of ASDs in the 6 Hz model, which collectively resembles clinical pathophysiology of temporal lobe epilepsy. The work reported in this thesis opens new avenues and provides much needed research tools for future ASDs discovery.
|Date of Award||21 Feb 2017|
|Supervisor||Ilse Smolders (Promotor), Rafal Kaminski (Co-promotor), Joeri Aerts (Jury), Dimitri De Bundel (Jury), Mathieu Vinken (Jury), Wolfgang Löscher (Jury) & Corinne Roucard (Jury)|