ArticleProceedings of the National Academy of Sciences of the United States of America2017
NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04776499 (Clinical Evaluation in Healthy Volunteers of Potential syneRgistic Vascular Effects of PrOpylthiouracil, Riociguat, and Perphenazine a Possible STROKE Medication), which is not on this map. Cited by 83 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical Evaluation in Healthy Volunteers of Potential syneRgistic Vascular Effects of PrOpylthiouracil, Riociguat, and Perphenazine a Possible STROKE Medication
Who cites it
83 citing papers in PubMed, 3 syntheses or guidelines pooled it, 149 citations in OpenAlex.
- Therapeutic and adverse effects of adrenaline on patients who suffer out-of-hospital cardiac arrest: a systematic review and meta-analysis.European journal of medical research · 2023Pooled it
- Un-biased housekeeping gene panel selection for high-validity gene expression analysis.Scientific reports · 2022Pooled it
- Effects of epinephrine for out-of-hospital cardiac arrest: A systematic review and meta-analysis of randomized controlled trials.Medicine · 2019Pooled it
- The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial.Intensive care medicine · 2020Trial
- NADPH oxidases in immunometabolism and disease pathology: mechanistic networks, pollutant triggers, and therapeutic frontiers.Cellular & molecular immunology · 2026Review
- Article
- Review
- Overcoming Oxidative Stress in Parkinson's Disease: NADPH Oxidase 4 (NOX4) as a Potential Therapeutic Target.Antioxidants (Basel, Switzerland) · 2026Review
- Role of NADPH Oxidases as Novel Therapeutic Targets for the Impaired Neurovascular Unit in the Early Stage of Diabetic Retinopathy.International journal of molecular sciences · 2026Review
- MicroRNA-9-5p Alleviates Oxidative Stress, Inflammation, and Apoptosis in Cerebral Ischemia-reperfusion Injury by Targeting NOX4Current molecular medicine · 2026Article
- MicroRNA-383-5p regulation of NADPH oxidase 4 alleviates hemorrhagic transformation and improves acute outcomes after endovascular recanalization in acute ischemic stroke.Frontiers in immunology · 2026Article
- From Defense to Disease: NADPH Oxidase in Cellular Function and Dysregulation.Journal of immunology research · 2026Review
- Dynamic Oxidative States: Interplay of Aging, Metabolic Stress, and Circadian Rhythms in Modulating Stroke Severity.Antioxidants (Basel, Switzerland) · 2025Review
- Human Neural Progenitor Cell-Derived Exosomes Deliver miR- 100 - 5p Targeting NOX4 mRNA to Alleviate Oxidative Stress in Acute Ischemia Injury.Molecular neurobiology · 2025Article
- p-Coumaric acid alleviates neuronal damage in ischemic stroke mice by promoting BACH1 nuclear export and degradation.Acta pharmacologica Sinica · 2025Article
- NADPH oxidases: redox regulation of cell homeostasis and disease.Physiological reviews · 2025Review
- Reactive oxygen species in hypertension.Nature reviews. Cardiology · 2025Review
- Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Targeting PI3K/Akt in Cerebral Ischemia Reperfusion Injury Alleviation: From Signaling Networks to Targeted Therapy.Molecular neurobiology · 2024Review
- The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: Antioxidants in clinical trials.Biochemical pharmacology · 2024Review
23 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood-brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.