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

  • ️Sun Jan 01 2012

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

Kim A Radermacher et al. Exp Transl Stroke Med. 2012.

Abstract

As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.

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Figures

Figure 1
Figure 1

Relevant NOX isoforms in stroke and their respective subunit requirements (adapted from[46]). NOX2, as well as NOX4, seem to be implicated in stoke. Known regulatory proteins are associated with individual isoforms. Activator proteins are coloured in green and organizing proteins in blue. Both isoforms form functional dimers with p22phox. p47phox phosphorylation subsequently causes the cytosolic subunits p47phox, p67phox, and p40phox to translocate into membranes and fuse with the catalytic subunit NOX2. This is followed by interaction between Rac and NOX2. Nox4 forms a dimer with p22phox. Although NOX4 does not appear to require additional regulators, recently some NOX4 binding proteins (DPI and PolDip2) have been discovered whose role needs to be further elucidated. Potential target sites of NADPH oxidase inhibitors are also shown in the scheme.

Figure 2
Figure 2

Schematic overview of NADPH oxidases implicated in stroke. The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. The figure shows a brain capillary in cross section, showing endothelial tight junctions and end-feet of astrocytes covering these capillaries. The figure also shows pericytes, neurons and microglial cells. Cerebral NOX activation and subsequent ROS generation contributes to BBB disruption, inflammation and postischemic neuronal injury.

Figure 3
Figure 3

NOX4 deletion confers neuroprotection during stroke[12]. The upper images show the TTC staining of coronal brain slices after cerebral I/R in WT, NOX1-, NOX2- and NOX4 KO mice on 24 hours after tMCAO (1 hour ischemia). The infarct volume (white region) is about 75% smaller in NOX4 deficient mice compared to the other mice, as also illustrated by the bar graph. Stroke experiments were also performed in female mice and in older animals, obtaining the same results.

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