Drug Combinations for Antiepileptogenesis

Prevention of epilepsy in patients at risk is an urgent global unmet need. In theory, the latent period between an epileptogenic brain insult and the onset of epilepsy may offer a therapeutic window to interfere with epileptogenesis. Numerous preclinical and a few clinical studies on antiepileptogenesis have been performed in the past 20-plus years. The vast majority of these studies used treatments with single, often highly selective drugs shortly after epileptogenic brain injuries, mostly without any success. The negative results may be due to the complex mechanisms of epileptogenesis, which complicate any strategy to interfere with this process. It was therefore proposed to apply principles of network pharmacology to the search for antiepileptogenic treatments. Here the outcome of preclinical studies using rationally chosen drug combinations for antiepileptogenesis is reviewed. Of 24 drug combinations that are discussed here, only four exerted persistent antiepileptogenic efficacy in rodent models of acquired epilepsy. For three of these effective combinations, clinically approved drugs were used, which would facilitate translation into clinical trials. The chapter also discusses future advancements in the search for antiepileptogenic drugs or drug combinations, including the subsequent use of in silico, in vitro, and in vivo platforms as well as “big data” mining approaches and machine learning.