title: Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.
abstract: 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.
authors.affiliation: Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany. christoph.kleinschnitz@mail.uni-wuerzburg.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Henrike
authors.initials: H
authors.lastname: Grund
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Armitage
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: Manish
authors.initials: M
authors.lastname: Mittal
authors.forename: David
authors.initials: D
authors.lastname: Barit
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Konstanze
authors.initials: K
authors.lastname: Barthel
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Sabine
authors.initials: S
authors.lastname: Meurer
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse