Kleinschnitz, C; Grund, H; Wingler, K; Armitage, ME; Jones, E; Mittal, M; Barit, D; Schwarz, T; Geis, C; Kraft, P; Barthel, K; Schuhmann, MK; Herrmann, AM; Meuth, SG; Stoll, G; Meurer, S; Schrewe, A; Becker, L; Gailus-Durner, V; Fuchs, H; Klopstock, T; de Angelis, MH; Jandeleit-Dahm, K; Shah, AM; Weissmann, N; Schmidt, HHHW
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.
