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Review
. 2012 Jul;69(14):2345-63.
doi: 10.1007/s00018-012-1011-8. Epub 2012 May 23.

NADPH oxidases as therapeutic targets in ischemic stroke

Timo Kahles  1 , Ralf P Brandes
Affiliations
Review

NADPH oxidases as therapeutic targets in ischemic stroke

Timo Kahles et al. Cell Mol Life Sci. 2012 Jul.

Abstract

Reactive oxygen species (ROS) act physiologically as signaling molecules. In pathological conditions, such as ischemic stroke, ROS are released in excessive amounts and upon reperfusion exceed the body's antioxidant detoxifying capacity. This process leads to brain tissue damage during reoxygenation. Consequently, antioxidant strategies have long been suggested as a therapy for experimental stroke, but clinical trials have not yet been able to promote the translation of this concept into patient treatment regimens. As an evolution of this concept, recent studies have targeted the sources of ROS generation-rather than ROS themselves. In this context, NADPH oxidases have been identified as important generators of ROS in the cerebral vasculature under both physiological conditions in general and during ischemia/reoxygenation in particular. Inhibition of NADPH oxidases or genetic deletion of certain NADPH oxidase isoforms has been found to considerably reduce ischemic injury in experimental stroke. This review focuses on recent advances in the understanding of NADPH oxidase-mediated tissue injury in the cerebral vasculature, particularly at the level of the blood-brain barrier, and highlights promising inhibitory strategies that target the NADPH oxidases.

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Figures

Fig. 1
Fig. 1
Targets of reperfusion injury at the neurovascular unit: anatomical structure (bold), mechanism (italic), and effect (regular). EC Endothelial cell, BL basal lamina, MMP matrix metalloproteinases, TJ tight junction
Fig. 2
Fig. 2
Strategies of NADPH oxidase (Nox) inhibition in ischemic stroke. PPAR Peroxisome proliferator-activated receptor, AT1RB angiotensin II 1 receptor blocker (e.g., candesartan), ACE-Inhib angiotensin-converting enzyme inhibitor, AT1R angiotensin II 1 receptor, PKC protein kinase C, CK2 casein kinase 2, TcdB Clostridium difficile lethal toxin B, Statins HMG-CoA-reductase inhibitor (e.g., atorvastatin), DPI diphenylene iodonium
See this image and copyright information in PMC

Comment in

  • VAS2870 is a pan-NADPH oxidase inhibitor.
    Wingler K, Altenhoefer SA, Kleikers PW, Radermacher KA, Kleinschnitz C, Schmidt HH. Wingler K, et al. Cell Mol Life Sci. 2012 Sep;69(18):3159-60. doi: 10.1007/s00018-012-1107-1. Epub 2012 Aug 9. Cell Mol Life Sci. 2012. PMID: 22875281 Free PMC article. No abstract available.

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