New approaches for developing multi-targeted drug combinations for disease modification of complex brain disorders....

Over decades, the prevailing standard in drug discovery was the concept of designing highly selective compounds that act on individual drug targets. However, more recently, multi-target and combinatorial drug therapies have become an important treatment modality in complex diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The development of such network-based approaches is facilitated by the significant advance in our understanding of the pathophysiological processes in these and other complex brain diseases and the adoption of modern computational approaches in drug discovery and repurposing. However, although drug combination therapy has become an effective means for the symptomatic treatment of many complex diseases, the holy grail of identifying clinically effective disease-modifying treatments for neurodegenerative and other brain diseases remains elusive. Thus, despite extensive research, there remains an urgent need for novel treatments that will modify the progression of the disease or prevent its development in patients at risk. Here we discuss recent approaches with a focus on multi-targeted drug combinations for prevention or modification of epilepsy. Over the last ~10 years, several novel promising multi-targeted therapeutic approaches have been identified in animal models. We envision that synergistic combinations of repurposed drugs as presented in this review will be demonstrated to prevent epilepsy in patients at risk within the next 5-10 years.