Abstracts

Rationale: Prevention or modification of changes occurring during epileptogenesis after an initiating brain insult is a major unmet clinical need in patients at risk of developing epilepsy. Up to date, several drugs have been tested for epilepsy prevention, but preclinical trials were either negative or showed only disease-modifying effects, and clinical trials were not able to identify any epilepsy-preventing drug either. Considering the multiple mechanisms occurring during epileptogenesis, multitargeted strategies were proposed (“network pharmacology”) as a novel approach to identify antiepileptogenic treatments. The preclinical development of novel combinations of clinically approved drugs with diverse mechanisms of action that potentially influence epileptogenesis is an innovative approach to generate antiepileptogenic therapies for rapid translation into clinic. Here, levetiracetam, an antiepileptic drug which already showed disease-modifying effects in clinical trials, was tested with various combination partners for their antiepileptogenic efficacy. Methods: Following demonstration of tolerability, the antiepileptogenic efficacy of the four multitargeted drug combinations A, levetiracetam + topiramate; B, levetiracetam + phenobarbital; C, levetiracetam + parecoxib + anakinra and D, levetiracetam + atorvastatin + ceftriaxone was assessed in the intrahippocampal kainate mouse model. After induction of status epilepticus (SE), male NMRI-mice were treated with one of the drug combinations or vehicle over 5 days t.i.d. 4 and 12 weeks post-SE, continuous (24/7) EEG- and video-monitoring over 7 subsequent days was performed and both electrographic and electroclinical seizures were analysed to evaluate the antiepileptogenic efficacy. Thereafter, neurodegeneration was determined. Experiments with drug combinations A and B were repeated once to determine whether drug effects were reproducible. Moreover, µMRI and PET scanning were performed with combination A to identify antiepileptogenic mechanisms of the treatment. Results: The multitargeted drug combination A, levetiracetam + topiramate significantly reduced the incidence and frequency of electroclinical seizures developing after drug washout, indicating a disease-modifying effect, whereas such an effect was not observed using the other three multitargeted drug combinations. Furthermore, no antiepileptogenic or disease-modifying effect could be observed in mice treated with either levetiracetam or topiramate alone. Imaging experiments were not able to elucidate the underlying mechanism of the treatment with combination A. Conclusions: The data demonstrate that testing multitargeted drug combinations in the intrahippocampal kainate mouse model is a promising and relatively fast approach to face the urgent clinical need of generating antiepileptogenic therapies for patients at risk. Funding: Funded by the European Seventh´s Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET).