Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice
Article first published online: 23 JAN 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 156, Issue 4, pages 680–688, February 2009
How to Cite
Jackman, K., Miller, A., De Silva, T., Crack, P., Drummond, G. and Sobey, C. (2009), Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. British Journal of Pharmacology, 156: 680–688. doi: 10.1111/j.1476-5381.2008.00073.x
- Issue published online: 17 FEB 2009
- Article first published online: 23 JAN 2009
- Received 18 September 2008; revised 16 October 2008; accepted 23 October 2008
- cerebral ischaemia;
- NADPH oxidase;
Background and purpose: 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.
Experimental approach: 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.
Key results: 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.
Conclusions and implications: Apocynin improves outcome following stroke when administered before ischaemia in wild-type but not Nox2−/− mice.