Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke

Ana I. Casas, Pamela W. M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabe de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, Harald H. H. W. Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)
32 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)1772-1778
Number of pages7
JournalJournal of Clinical Investigation
Volume129
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • NADPH OXIDASE
  • INDEPENDENT PREDICTOR
  • THERAPEUTIC TARGETS
  • NEUROPROTECTION
  • ANGIOGENESIS
  • INJURY
  • COUNT

Cite this