Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration
Open accessAbstract
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
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VAS2870 appears to inhibit all isoforms, with proven inhibitory effects at least for NOX1, NOX2, NOX4, and NOX5 isoforms.
“VAS2870 appears to inhibit all isoforms, with proven inhibitory effects at least for NOX1, NOX2, NOX4, and NOX5 isoforms (21, 520).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [520]
VAS2870 and VAS3947 do not have a noticeable effect on XO- or eNOS-dependent ROS production, so they can be considered specific pan-NOX inhibitors.
“These inhibitors do not have a noticeable effect on XO- or eNOS-dependent ROS production, so they can be considered specific pan-NOX inhibitors.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [520]
Oxidative stress plays a key role in organ complications of diabetes such as cardiovascular problems, stroke, diabetic retinopathy, nephropathy, and neuropathy; diabetic nephropathy is most common, affecting 28% of the diabetic population.
“Regardless of whether excessive ROS formation is the primary initiator or accompanying factor in the pathogenesis of diabetes mellitus, oxidative stress plays a key role in the organ complications such as cardiovascular problems, neurological problems (stroke), diabetic retinopathy, nephropathy, and neuropathy; diabetic nephropathy being the most common, affecting 28% of the diabetic population (J”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Kleinschnitz et al. 2010
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Nox1, 2, 4, 5: Counting out oxidative stress
Wingler, K., Hermans, J., Schiffers, P., Moens, A., Paul, M., & Schmidt, H. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01249.x · Cited by 113 · see citing works
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- Authors
- Kleinschnitz, C., Grund, H., Wingler, K., Armitage, M. E., Jones, E., Mittal, M., Barit, D., Schwarz, T., Geis, C., Kraft, P., Barthel, K., Schuhmann, M. K., Herrmann, A. M., Meuth, S. G., Stoll, G., Meurer, S., Schrewe, A., Becker, L., Gailus-Durner, V., Fuchs, H., Klopstock, T., de Angelis, M. H., Jandeleit-Dahm, K., Shah, A. M., Weissmann, N., & Schmidt, H. H. H. W.
- Affiliations
- University of Würzburg (DE)
- Justus-Liebig-Universität Gießen (DE)
- Florey Institute of Neuroscience and Mental Health (AU)
- Monash University (AU)
- Baker Heart and Diabetes Institute (AU)
- University of Göttingen (DE)
- University of Münster (DE)
- Helmholtz Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- King's College London (GB)
- Corresponding author
- Kleinschnitz, Christoph
- Schmidt, Harald H. H. W.
- ORCID
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-21
- Volume
- 8
- Issue
- 9
- Pages
- e1000479
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC2943442
- OpenAlex
- W2165393084
- Cited by
- 447
- References
- 59
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 15 · 2023: 18 · 2022: 25 · 2021: 28 · 2020: 21 · 2019: 31 · 2018: 39 · 2017: 31 · 2016: 29 · 2015: 24 · 2014: 42 · 2013: 46 · 2012: 46
- FWCI
- 25.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, cc-by)
- Site cant be reached (submittedVersion, cc-by)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- GRO (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Albert-Ludwigs-Universität Freiburg
- Université de Genève
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- ischemic stroke, oxidative stress, neuroprotection, VAS2870, cerebral ischemia, blood-brain barrier disruption, neuronal apoptosis
- MeSH terms
- NADPH Oxidase 4, Animals, Blood-Brain Barrier, Brain, Female, Male, Phenotype, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Stroke, Mice
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