title: Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress.
abstract: CONCLUSIONS
  Stroke, a leading cause of death and disability, poses a substantial burden for patients, relatives, and our healthcare systems. Only one drug is approved for treating stroke, and more than 30 contraindications exclude its use in 90% of all patients. Thus, new treatments are urgently needed. In this review, we discuss oxidative stress as a pathomechanism of poststroke neurodegeneration and the inhibition of its source, type 4 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), as a conceptual breakthrough in stroke therapy.
  
  
  BACKGROUND
  Among potential sources of reactive oxygen species (ROS), the NOXes stand out as the only enzyme family that is solely dedicated to forming ROS. In rodents, three cerebrovascular NOXes exist: the superoxide-forming NOX1 and 2 and the hydrogen peroxide-forming NOX4. Studies using NOX1 knockout mice gave conflicting results, which overall do not point to a role for this isoform. Several reports find NOX2 to be relevant in stroke, albeit to variable and moderate degrees. In our hands, NOX4 is, by far, the major source of oxidative stress and neurodegeneration on ischemic stroke.
  
  
  RESULTS
  We critically discuss the tools that have been used to validate the roles of NOX in stroke. We also highlight the relevance of different animal models and the need for advanced quality control in preclinical stroke research.
  
  
  CONCLUSIONS
  The development of isoform-specific NOX inhibitors presents a precious tool for further clarifying the role and drugability of NOX homologues. This could pave the avenue for the first clinically effective neuroprotectant applied poststroke, and even beyond this, stroke could provide a proof of principle for antioxidative stress therapy.
authors.affiliation: Department of Pharmacology, Maastricht University, Maastricht, The Netherlands. k.radermacher@maastrichtuniversity.nl
authors.forename: Kim A
authors.initials: KA
authors.lastname: Radermacher
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.forename: Friederike
authors.initials: F
authors.lastname: Langhauser
authors.forename: Sebastian
authors.initials: S
authors.lastname: Altenhöfer
authors.forename: Pamela
authors.initials: P
authors.lastname: Kleikers
authors.forename: J J Rob
authors.initials: JJ
authors.lastname: Hermans
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000201:enzymology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D055786:Gene Knockout Techniques; D006801:Humans; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012107:Research Design / Q000592:standards
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human