NOX5 as a therapeutic target in cerebral ischemic injury
Luciana Simão do Carmo, … , Bradford C. Berk, David G. Harrison
Luciana Simão do Carmo, … , Bradford C. Berk, David G. Harrison
Published April 1, 2019; First published March 18, 2019
Citation Information: J Clin Invest. 2019;129(4):1530-1532. https://doi.org/10.1172/JCI127682.
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Commentary

NOX5 as a therapeutic target in cerebral ischemic injury

Abstract

In this issue of the JCI, Casas et al. define a previously unknown role of the NADPH oxidase catalytic subunit NOX5 in cerebral infarction. Using a mouse expressing human NOX5 in the endothelium, the investigators show that NOX5 is activated and plays a deleterious role in promoting edema, infarction, and ultimately, worsened neurological function following cerebral ischemia. They provide evidence that this is due to the breakdown of the blood-brain barrier (BBB) and that a unique pharmacological inhibitor of NOX5, ML090, if given early, around the time of reoxygenation, can maintain BBB integrity. Future studies of NOX5 inhibition in humans, particularly in the setting of thrombolysis, are warranted.

Authors

Luciana Simão do Carmo, Bradford C. Berk, David G. Harrison

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Figure 1

The role of NOX5 in BBB breakdown.

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The role of NOX5 in BBB breakdown. (A) Schematic of the NOX5 protein con...
(A) Schematic of the NOX5 protein containing calcium-binding (EF-hand) and NADPH- and FAD-binding sites. (B) Under normal conditions, the BBB has tight paracellular junctions and low permeability. Upon ischemia/reperfusion, intracellular calcium increases, leading to the activation of NOX5 and production of ROS including superoxide (O2–), peroxynitrite (OONO–), and hydrogen peroxide (H2O2). These promote loss of BBB integrity, leading to the entry of injurious macromolecules, inflammatory cells, and other toxins that cause progressive brain injury. Illustration by Rachel Davidowitz.