Abstract
We tested the effect of apocynin, an NADPH oxidase inhibitor, on cerebral artery production of superoxide (O2‐) and hydrogen peroxide (H2O2), and on stroke outcome in C57Bl6/J and Nox2 KO mice. Apocynin (300 μM) inhibited NADPH‐induced O2‐ production by ∼40% (n=9, P<0.05), and reduced H2O2 levels by ∼80% (n=6, P<0.05), in cerebral arteries. Interestingly, apocynin also reduced detectable H2O2 by >80% in the absence of arterial tissue. Ischemic stroke was induced by 30 min middle cerebral artery occlusion (n=79). Mice received vehicle (0.1% DMSO), 2.5 or 5 mg/kg apocynin ip 30 min before ischemia. Mortality at 24 h was 12% in vehicle controls, and 0% (P=0.24) and 41% (P<0.05) in mice treated with 2.5 and 5 mg/kg apocynin, respectively. Infarct volume was reduced by 2.5 mg/kg apocynin by ∼50% (n=8; P<0.05), whereas 5 mg/kg apocynin was ineffective (n=13). Apocynin (2.5 mg/kg) had no effect on infarct volume in Nox2 KO mice, suggesting its protective effect is Nox2‐dependent. Thus, apocynin inhibits cerebral NADPH oxidase, directly scavenges H2O2, and has a narrow therapeutic window for stroke. As H2O2 is an endogenous cerebral vasodilator, high dose apocynin could compromise blood flow.
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