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

ABSTRACT: Ischemic 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 calcium-activated, 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 NOX5-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenation-induced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.

SUBMITTER: Casas AI

PROVIDER: S-EPMC6436900 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Casas Ana I AI Kleikers Pamela Wm PW Geuss Eva E Langhauser Friederike F Adler Thure T Busch Dirk H DH Gailus-Durner Valerie V de Angelis Martin Hrabê MH Egea Javier J Lopez Manuela G MG Kleinschnitz Christoph C Schmidt Harald Hhw HH

The Journal of clinical investigation 20190318 4

Ischemic 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 calcium-activated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found tha ...[more]

PMID: 30882367

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Project description:BackgroundBlood-brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer's disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).MethodsFor this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (Ktrans) were calculated within regions of interest. Spearman's correlation and multivariate linear regression were applied to analyze associations between Ktrans and specific clinical characteristics.ResultsIn members of the DLB (vs HC) group, Ktrans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and Ktrans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased Ktrans values of parietal ( β = 0.391; p = 0.001) and occipital ( β = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased Ktrans values of cerebral cortex ( β = 0.285; p = 0.015), frontal lobe ( β = 0.237; p = 0.043), and parietal lobe ( β = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments.ConclusionBBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity.

Dataset Information

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

Publications

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

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