Small molecule inhibiting microglial nitric oxide release could become a potential treatment for neuroinflammation
Philipp Jordan, Amanda De Andrade Costa, Edgar Specker, Oliver Popp, Andrea Volkamer, Regina Piske, Tessa Obrusnik, Sabrina Kleissle, Kevin Stuke, André Rex, Martin Neuenschwander, Jens Peter von Kries, Marc Nazaré, Phillip Mertins, Helmut Kettenmann, Susanne A. Wolf
Abstract
Microglia are the immune effector cells of the central nervous system (CNS) and react to pathologic events with a complex process including the release of nitric oxide (NO). NO is a free radical, which is toxic for all cells at high concentrations. To target an exaggerated NO release, we tested a library of 16 544 chemical compounds for their effect on lipopolysaccharide (LPS)-induced NO release in cell line and primary neonatal microglia. We identified a compound (C1) which significantly reduced NO release in a dose-dependent manner, with a low IC50 (252 nM) and no toxic side effects in vitro or in vivo. Target finding strategies such as in silico modelling and mass spectroscopy hint towards a direct interaction between C1 and the nitric oxide synthase making C1 a great candidate for specific intra-cellular interaction with the NO producing machinery.