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bioRxiv · 10.1101/359893

Calcium-dependent reactive oxygen formation and blood-brain barrier breakdown by NOX5 limits post-reperfusion outcome in stroke

Casas, A. I.·Kleikers, P. W.·Geuss, E.·Langhauser, F.·Egea, J.·Lopez, M. G.·Kleinschnitz, C.·Schmidt, H. H.
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Abstract

Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic options. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain-barrier. Its mechanism, however, is unknown. Here we identify type 5 NADPH oxidase (NOX5), a calcium-activated, reactive oxygen species (ROS)-forming enzyme as missing link. Using a humanised knock-in mouse model and in vitro in organotypic cultures, we find re-oxygenation or calcium overload to increase brain ROS levels in a NOX5-dependent manner. In vivo, post-ischemic ROS formation, infarct volume and functional outcomes were worsened in NOX5 knock-in mice. Of clinical and therapeutic relevance, in a human blood-barrier model pharmacological NOX inhibition also prevented acute re-oxygenation induced leakage. Our data therefore identify NOX5 as sufficient to induce acute post-reperfusion calcium-dependent blood-brain-barrier breakdown. We suggest urgent clinical validation by conducting protective post-stroke re-canalisation in the presence of a NOX inhibitor.

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Casas, A. I., Kleikers, P. W., Geuss, E., Langhauser, F., Egea, J., Lopez, M. G., Kleinschnitz, C., Schmidt, H. H.. 2018-06-30. Calcium-dependent reactive oxygen formation and blood-brain barrier breakdown by NOX5 limits post-reperfusion outcome in stroke. https://doi.org/10.1101/359893

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