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. 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.
Kleinschnitz
Christoph
C
Neurologische Klinik und Poliklinik, Universität Würzburg, Würzburg, Germany. christoph.kleinschnitz@mail.uni-wuerzburg.de
Grund
Henrike
H
Wingler
Kirstin
K
Armitage
Melanie E
ME
Jones
Emma
E
Mittal
Manish
M
Barit
David
D
Schwarz
Tobias
T
Geis
Christian
C
Kraft
Peter
P
Barthel
Konstanze
K
Schuhmann
Michael K
MK
Herrmann
Alexander M
AM
Meuth
Sven G
SG
Stoll
Guido
G
Meurer
Sabine
S
Schrewe
Anja
A
Becker
Lore
L
Gailus-Durner
Valérie
V
Fuchs
Helmut
H
Klopstock
Thomas
T
de Angelis
Martin Hrabé
MH
Jandeleit-Dahm
Karin
K
Shah
Ajay M
AM
Weissmann
Norbert
N
Schmidt
Harald H H W
HH
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
D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse