Systems biology-based drug repurposing for neuroinflammation treatment in activated human microglia

Neuroinflammation is a physiological response triggered by alterations in tissue homeostasis within the Central Nervous System (CNS); depending on the magnitude and chronicity of inflammation, it is considered a common state in the pathophysiology of several neurodegenerative and psychiatric diseases. Neuroinflammation is a very complex and context-dependent condition, mediated by the activity of several pathways and molecules, thus the search of valuable targets and therapeutic strategies is a priority. This study proposes a systems biology approach to create a data network about genes, drugs, and related targets in the context of human neuroinflammation to identify new potential repurposed drug candidates. Each candidate drug was associated with a score that considered both the topological properties of the network and the biological functions of the proteins. The computational pipeline identified Fostamatinib as a potential repurposed candidate in neuroinflammation. To confirm the computational results, R406, the active metabolite of Fostamatinib inhibiting the Syk pathway, was assessed in two different human microglial in vitro models to verify its potential beneficial effects. Results evidenced the efficacy of R406 in counteracting the pro-inflammatory response in both models.