Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase.
OBJECTIVE
Free radicals account for a significant proportion of the brain damage that occurs during ischemic stroke. Using mutant mice (X-CGD) with a dysfunctional phagocytic NADPH oxidase, we investigated the role of this superoxide-generating enzyme as a mediator of the reperfusion injury in a mouse model of middle cerebral artery occlusion.


METHODS
Transient (2 hour) middle cerebral artery occlusion was performed in X-CGD or wild-type litter mates (8- to 10-week-old). After 22 hours of reperfusion, brains were harvested and infarct volume delineated using 2,3,5-triphenyl-tetrazolium chloride. To elucidate the origin of the damaging NADPH oxidase, transient ischemia was also performed in X-CGD or wild-type mice transplanted with wild-type C57 B1/6J or X-CGD bone marrow, respectively.


RESULTS
The infarct volume induced by transient ischemia was significantly less in X-CGD mice (29.1 +/- 5.6 mm3; n = 13) than wild-type littermates (54.0 +/- 10.6 mm3; n = 10; P < .05). The elimination of a functional NADPH oxidase from either the circulation or the central nervous system, by performing the appropriate bone marrow transplant experiments, did not reduce the infarct size induced by transient ischemia. This suggests that in order to confer protection against transient ischemia and reperfusion, a putative neuronal and circulating NADPH oxidase need to be inactivated.


CONCLUSIONS
Brain injury was reduced in mice lacking a functional NADPH oxidase in both the central nervous system and peripheral leukocytes, suggesting a pivotal role for the NADPH oxidase in the pathogenesis of ischemia-reperfusion injury in the brain.
Walder
C E
CE
Department of Cardiovascular Research, Genentech Inc., South San Francisco, Calif., USA. cwalder@elr1.co.uk
Green
S P
SP
Darbonne
W C
WC
Mathias
J
J
Rae
J
J
Dinauer
M C
MC
Curnutte
J T
JT
Thomas
G R
GR
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology*; D002544:Cerebral Infarction / Q000473:pathology*; D004789:Enzyme Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009154:Mutation; D019255:NADPH Oxidases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D019255:NADPH Oxidases