RATIONAL DEVELOPMENT OF PDE9A-TARGETING COMPOUNDS TO MITIGATE NEUROINFLAMMATION: A COMBINED COMPUTATIONAL AND IN VITRO STUDY

Oxidative stress and inflammation are key players in central nervous system (CNS) diseases, and in neurodegeneration. The aim of this study was to evaluate the anti-inflammatory effect of potential inhibitors of phosphodiesterase 9 (PDE9) a target of growing interest in CNS diseases, by using a multidisciplinary approach.The compounds were selected by virtual screening and molecular docking. Then the most potent enzymatic inhibitors of PDE9 were tested in an in vitro model of neuroinflammation represented by glia cell exposed to LPS. The levels of the following pro-inflammatory proteins and genes were quantified: IL-1β, COX-2, and phospho-NF-κB p65 (p-p65) through Western blotting (WB) and interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) through quantitative real-time polymerase chain reaction (RT-qPCR).When present in the incubation medium, the PDE9 inhibitors reduced the increased levels of pro-inflammatory genes (IL-1β, IL-6 and TNFα) and proteins (IL-1β, COX-2, and p-NF-kB) induced by LPS. The results of this multidisciplinary study underscore the potential of developing PDE9A inhibitors to modulate cyclic guanosine monophosphate (cGMP) signalling pathways implicated in synaptic plasticity, cognitive functions, and neuroinflammation identify the PDE9 as new therapeutic target.