Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 156, Issue 4, Pages 680-688Publisher
WILEY
DOI: 10.1111/j.1476-5381.2008.00073.x
Keywords
cerebral ischaemia; NADPH oxidase; Nox2; apocynin; superoxide
Categories
Funding
- National Health and Medical Research Council of Australia (NHMRC) [208969, 350477]
- University of Melbourne Research Grant Scheme
- NHMRC Dora Lush Biomedical Research Scholarship
- High Blood Pressure Research Council Of Australia Postdoctoral Fellow
- Australian Postgraduate Award
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Reactive oxygen species (ROS) derived from Nox2-containing reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is reportedly detrimental in cerebrovascular disease. However, ROS generation by other Nox isoforms may have a physiological role. No Nox2-selective inhibitors have yet been identified, and thus it is unclear whether isoform non-selective Nox inhibitors would necessarily improve outcome after stroke. We assessed the effect of apocynin on cerebrovascular ROS production and also on outcome following cerebral ischaemia when administered either before ischaemia or after cerebral reperfusion. The involvement of Nox2-containing NADPH oxidase in the effects of apocynin was assessed using Nox2(-/-) mice. Transient cerebral ischaemia was induced by 0.5 h middle cerebral artery occlusion followed by 23.5 h reperfusion. Mice received apocynin (2.5 mg.kg(-1), i.p.) either 0.5 h before ischaemia or 1 h after reperfusion. In situ superoxide production after cerebral ischaemia-reperfusion was measured in brain sections of wild-type mice at 24 h using dihydroethidium fluorescence. Treatment with apocynin 0.5 h before ischaemia reduced total infarct volume, neurological impairment and mortality in wild-type but not Nox2(-/-) mice. Conversely, treatment with apocynin 1 h after initiation of reperfusion had no protective effect. Cerebral ischaemia and reperfusion increased superoxide production in the brain at 24 h, and pretreatment but not posttreatment with apocynin reduced superoxide levels. Apocynin improves outcome following stroke when administered before ischaemia in wild-type but not Nox2(-/-) mice.
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