Abstracts

Rationale: A large variety of brain insults can induce temporal lobe epilepsies. The latent period following the initial insult is characterised by multiple molecular, structural and functional changes (epileptogenesis) which lead to spontaneous recurrent seizures (SRS). The prevention or modification of these changes (antiepileptogenesis) in patients at risk is a major unmet clinical need. Several drugs have been tested in preclinical as well as clinical trials, but preclinical studies were either negative or showed only disease-modification (e.g. reduction of severity of SRS), and clinical studies failed to identify any epilepsy-preventing drug. In the majority of studies drugs were given as monotherapy. Considering the multiple mechanisms involved in epileptogenesis, multitargeted approaches were proposed ("network pharmacology") as an antiepileptogenic treatment strategy. The preclinical development of novel combinations of clinically approved drugs with diverse mechanisms is a novel approach to generate antiepileptogenic therapies for rapid translation into clinic. Methods: We developed an algorithm for testing drug combinations in a two-stage screening approach in mice and rats, based on the drug development phases in humans. First, we evaluated tolerability of 4 rationally chosen drug combinations: A) levetiracetam + topiramate, B) levetiracetam + phenobarbital, C) levetiracetam + parecoxib + anakinra, D) valproate + losartan + memantine. Except combination D, all combinations were relatively well tolerated in naive as well as in chronic epileptic and post-status epilepticus (SE) mice (Klee et al.2015, Epilepsy Res., 2015,118, 34-48). Theses combinations are currently under evaluation for antiepileptogenic efficacy in the mouse intrahippocampal kainate model. After induction of SE, male NMRI-mice are treated for 5 subsequent days 3 times daily with one of the drug combinations. After 4 and 12 weeks post-SE, continuous (24/7) EEG- and video-monitoring over 7 subsequent days is performed and both electrographic and electroclinical seizures are analysed to evaluate the antiepileptogenic efficacy. Thereafter, neurodegeneration is determined. Results: First experiments with the multitargeted drug combinations are currently evaluated and data will be presented at the meeting. If a combination effectively prevents or modifies post-SE epilepsy in mice, it will be evaluated in a second epilepsy model in rats according to our two-stage approach. Furthermore, in addition to the four drug combinations described above, further combinations of clinically approved drugs will be included in our approach. Conclusions: Multitargeted drug combinations tested in the mouse intrahippocampal kainate model are a promising and relatively fast approach to face the urgent clinical need to generate antiepileptogenic therapies for patients at risk. First results indicate that such combinations might have a disease-modifying effect, but further studies are needed to confirm these findings Funding: Funded by the European Sevenths Framework Programme (GP7/2007-2013) under grant agreement n602102 (EPITARGET).