The 1027th target candidate in stroke: Will NADPH oxidase hold up?

One third of all patients do not survive a stroke, and in those who do, brain damage can be so severe that it results in life-long disability [1]. In this review, we will focus on ischemic stroke (87% of all stroke cases) and on both, the disturbed oxygen and nutrient supply to the infarcted region and the consequences of reperfusion.Neurons start dying already 5 minutes after lacking oxygen. The only approved treatment for acute stroke is an early intravenous administration of recombinant tissue plasminogen activator (rt-PA) to restore cerebral blood flow. However, even if blood flow is restored and no bleeding occurs, reperfusion can paradoxically aggravate neuronal damage. Mechanistically, reactive oxygen species (ROS) generated from the newly arriving oxygen, i.e. ischemia-reperfusion (I/R) injury, are thought to play a major role in this. Hence, to prevent brain damage after an ischemic stroke novel therapeutic strategies that specifically address this paradox are urgently needed.Unfortunately, despite tremendous research activities, all therapeutic strategies that at some stage showed promising results in pre-clinical animal models have finally failed before or in clinical testing [2]. A systematic review covering 8516 stroke-relevant studies added this up to 1026 candidate strategies finally failing [3]. 114 out of 1026 neuroprotective drugs were tested in patients, 42% even quite pre-maturely, i.e. before the results from animal testing were reported. On top of this, drugs that had been selected for clinical trials were not necessarily the most efficient ones based on animal data. This roadblock in stroke innovation [4] has raised fundamental concerns about the general approach and translatability of pre-clinical stroke research. Possible explanations for an impaired translatability are the divergences between pre-clinical animal models and the clinical situation in real patients [5]. Therefore, older animals with co-morbidities should be tested and actual c