Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.

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. Thu...

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Autores principales:	Christoph Kleinschnitz, Henrike Grund, Kirstin Wingler, Melanie E Armitage, Emma Jones, Manish Mittal, David Barit, Tobias Schwarz, Christian Geis, Peter Kraft, Konstanze Barthel, Michael K Schuhmann, Alexander M Herrmann, Sven G Meuth, Guido Stoll, Sabine Meurer, Anja Schrewe, Lore Becker, Valérie Gailus-Durner, Helmut Fuchs, Thomas Klopstock, Martin Hrabé de Angelis, Karin Jandeleit-Dahm, Ajay M Shah, Norbert Weissmann, Harald H H W Schmidt
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ca15ac39c2024783aa2cc40faf23366a
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spelling	oai:doaj.org-article:ca15ac39c2024783aa2cc40faf23366a2021-11-18T05:34:50ZPost-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.1544-91731545-788510.1371/journal.pbio.1000479https://doaj.org/article/ca15ac39c2024783aa2cc40faf23366a2010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20877715/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Ischemic 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.Christoph KleinschnitzHenrike GrundKirstin WinglerMelanie E ArmitageEmma JonesManish MittalDavid BaritTobias SchwarzChristian GeisPeter KraftKonstanze BarthelMichael K SchuhmannAlexander M HerrmannSven G MeuthGuido StollSabine MeurerAnja SchreweLore BeckerValérie Gailus-DurnerHelmut FuchsThomas KlopstockMartin Hrabé de AngelisKarin Jandeleit-DahmAjay M ShahNorbert WeissmannHarald H H W SchmidtPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 9 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K Schuhmann Alexander M Herrmann Sven G Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M Shah Norbert Weissmann Harald H H W Schmidt Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
description	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.
format	article
author	Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K Schuhmann Alexander M Herrmann Sven G Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M Shah Norbert Weissmann Harald H H W Schmidt
author_facet	Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K Schuhmann Alexander M Herrmann Sven G Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M Shah Norbert Weissmann Harald H H W Schmidt
author_sort	Christoph Kleinschnitz
title	Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
title_short	Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
title_full	Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
title_fullStr	Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
title_full_unstemmed	Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
title_sort	post-stroke inhibition of induced nadph oxidase type 4 prevents oxidative stress and neurodegeneration.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/ca15ac39c2024783aa2cc40faf23366a
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Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.

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