NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice.
Reactive oxygen species (ROS) are mediators of brain injury in ischemia/reperfusion. An involvement of the NADPH oxidase Nox2 has been demonstrated. In contrast, only little is known about the contribution of the Nox1 homologue in this context. Thus, we studied the role of Nox1 in early cerebral reperfusion injury in the middle cerebral artery filament occlusion model using Nox1 knockout mice. Genetic deletion of a functional Nox1 lead to a 55% attenuation in lesion size at 24h after induction of 1h ischemia (p<0.05). This result was paralleled by a significant improvement of neurological outcome, preservation of blood-brain barrier integrity and reduced cerebral edema in Nox1(y/)(-) compared to WT mice. Interestingly, no difference in infarct size between WT and Nox1(y/)(-) was observed with an occlusion time of 2h and longer. Apoptosis rate as measured by TUNEL staining was similar between the groups. Moreover, infusion of the antioxidant TEMPOL as well as of the unspecific NO-synthase inhibitor l-NAME elicited similar changes with respect to ischemic tissue damage between WT and Nox1-deficient mice. In conclusion, Nox1 is involved in the pathophysiology of cerebral ischemia. Our data however indicate that ROS-mediated direct cellular injury is unlikely to explain the protective effect achieved by genetic deletion of the enzyme.
Kahles
Timo
T
Department ofNeurology, University Hospital, Goethe-University Frankfurt, Frankfurt/Main, Germany. t.kahles@em.uni-frankfurt.de
Kohnen
Andreas
A
Heumueller
Sabine
S
Rappert
Angelika
A
Bechmann
Ingo
I
Liebner
Stefan
S
Wittko
Ina M
IM
Neumann-Haefelin
Tobias
T
Steinmetz
Helmuth
H
Schroeder
Katrin
K
Brandes
Ralf P
RP
D000818:Animals; D020520:Brain Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074624:NADPH Oxidase 1; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020521:Stroke / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse