Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (
levetiracetam and
topiramate) for which in silico analysis of
drug-protein interaction networks indicated a synergistic effect on a large functional network of
epilepsy-relevant
proteins. Using the intrahippocampal
kainate mouse model of
temporal lobe epilepsy, the
drug combination was administered during the latent period before onset of spontaneous recurrent
seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single
drug treatment. Furthermore, a combination of
levetiracetam and
phenobarbital, for which in silico analysis of
drug-protein interaction networks did not indicate any significant
drug-drug interaction, was not effective to modify development of
epilepsy. Surprisingly, the promising antiepileptogenic effect of the
levetiracetam/
topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput
RNA-sequencing (
RNA-seq) of the ipsilateral hippocampus of mice treated with the
levetiracetam/
topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of
epilepsy.