NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia.
Medium spiny neurons (MSNs) constitute most of the striatal neurons and are known to be vulnerable to ischemia; however, the mechanisms of the vulnerability remain unclear. Activated forms of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX), which require interaction between cytosolic and membrane-bound subunits, are among the major sources of superoxide in the central nervous system. Although increasing evidence suggests that NOX has important roles in neurodegenerative diseases, its roles in MSN injury after transient global cerebral ischemia (tGCI) have not been elucidated. To clarify this issue, C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion for 22 minutes. Western blot analysis revealed upregulation of NOX subunits and recruitment of cytosolic subunits to the cell membrane at early (3 to 6 hours) and late (72 hours) phases after tGCI. Taken together with immunofluorescent studies, this activation arose in MSNs and endothelial cells at the early phase, and in reactive microglia at the late phase. Pharmacological and genetic inhibition of NOX attenuated oxidative injury, microglial activation, and MSN death after tGCI. These findings suggest that NOX has pivotal roles in MSN injury after tGCI and could be a therapeutic target for brain ischemia.
Yoshioka
Hideyuki
H
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
Niizuma
Kuniyasu
K
Katsu
Masataka
M
Okami
Nobuya
N
Sakata
Hiroyuki
H
Kim
Gab Seok
GS
Narasimhan
Purnima
P
Chan
Pak H
PH
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology; D002339:Carotid Arteries; D002462:Cell Membrane / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology* / Q000473:pathology*; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000201:enzymology* / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*; D011971:Receptors, Immunologic / Q000172:deficiency; D013997:Time Factors; D015854:Up-Regulation
D000098:Acetophenones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; C056165:acetovanillone; D019255:NADPH Oxidases