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Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke.
J. Clin. Invest. 129, 1772-1778 (2019)
lschemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calciumactivated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOXS-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenationinduced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calcium ; Hypoxia ; Neuroscience ; Pharmacology ; Therapeutics; Nadph Oxidase; Independent Predictor; Therapeutic Targets; Neuroprotection; Angiogenesis; Injury; Count
Institute(s) Institute of Experimental Genetics (IEG)