title: NADPH oxidase is involved in post-ischemic brain inflammation.
abstract: Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is widely expressed in brain tissue including neurons, glia, and endothelia in neurovascular units. It is a major source of oxidants in the post-ischemic brain and significantly contributes to ischemic brain damage. Inflammation occurs after brain ischemia and is known to be associated with post-ischemic oxidative stress. Post-ischemic inflammation also causes progressive brain injury. In this study we investigated the role of NOX2 in post-ischemic cerebral inflammation using a transient middle cerebral artery occlusion model in mice. We demonstrate that mice with NOX2 subunit gp91(phox) knockout (gp91 KO) showed 35-44% less brain infarction at 1 and 3 days of reperfusion compared with wild-type (WT) mice. Minocycline further reduced brain damage in the gp91 KO mice at 3 days of reperfusion. The gp91 KO mice exhibited less severe post-ischemic inflammation in the brain, as evidenced by reduced microglial activation and decreased upregulation of inflammation mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α, inducible nitric oxide synthases, CC-chemokine ligand 2, and CC-chemokine ligand 3. Finally, we demonstrated that an intraventricular injection of IL-1β enhanced ischemia- and reperfusion-mediated brain damage in the WT mice (double the infarction volume), whereas, it failed to aggravate brain infarction in the gp91 KO mice. Taken together, these results demonstrate the involvement of NOX2 in post-ischemic neuroinflammation and that NOX2 inhibition provides neuroprotection against inflammatory cytokine-mediated brain damage.
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Nobuya
authors.initials: N
authors.lastname: Okami
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D016207:Cytokines / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D019255:NADPH Oxidases; D008911:Minocycline