NADPH oxidases in ischemic stroke: cellular sources and pharmacological translation

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Despite tremendous research efforts, recombinant tissue plasminogen activator (rt- PA) is still the only approved compound for the treatment of acute ischemic stroke which represents the second leading cause of death worldwide. Reactive oxygen species (ROS) and oxidative stress are critically involved in the pathophysiology of stroke but their precise role is still unknown. One attractive candidate source for oxidative stress are NADPH oxidases, the only known enzyme family that has ROS as their sole enzymatic product. NADPH oxidases are oligomeric protein complexes, with the NOX subunit catalysing the entire reaction. In rodents 4 NOX genes exist, and in the rodent brain NOX are mainly expressed in neurons and the vasculature with NOX4 being the most abundant isoform. The aim of this project is to elucidate the role of NOX4 in the pathophysiology of ischemic stroke using genetically defined animal models. Transient and permanent cerebral ischemia will be applied to constitutive and tissue specific NOX4 knockout mice. The infarct dynamics will be determined by routine 1.5 T magnetic resonance imaging (MRI) and histology. The penumbra will be quantitatively assessed by using multimodal ultra-high field MRI (17.6 T) including diffusion- (DWI) and perfusion (PWI)-weighted sequences. Furthermore, we can image free radical formation ex vivo and in vivo using conventional techniques (dihydroethidium [DHE] and nitrotyrosine staining) as well as electron paramagnetic resonance imaging (EPRI) through cooperation with Bruker BioSpin GmbH, Karlsruhe, Germany and Prof. Dr. Harald Schmidt, Monash University, Melbourne, Australia. For translating our pathophysiological findings into therapeutic applications, the only specific NOX inhibitor (VAS2870) is available.