Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice
Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice
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DOI：
10.1111/j.1476-5381.2008.00073.x
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发表时间：
2009-02-01
影响因子：
7.3
通讯作者：
Sobey, C. G.
中科院分区：
文献类型：
--
作者：
Jackman, K. A.;Miller, A. A.;Sobey, C. G.
活性氧（ROS）来源于含有还原形式的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性的nox，据报道在脑血管疾病中是有害的。然而，其他Nox异构体产生的ROS可能具有生理作用。目前尚未发现Nox选择性抑制剂，因此尚不清楚异型非选择性Nox抑制剂是否一定会改善中风后的预后。我们评估了罗布麻素在缺血前或脑再灌注后对脑血管ROS产生的影响以及对脑缺血后预后的影响。使用Nox2（-/-）小鼠评估含有Nox2的NADPH氧化酶在罗布麻素作用中的作用。阻断大脑中动脉0.5 h，再灌注23.5 h，引起短暂性脑缺血。小鼠在缺血前0.5 h或再灌注后1 h分别给予罗布麻素（2.5 mg.kg(-1), i.p.）。采用二氢乙啶荧光法测定野生型小鼠脑缺血再灌注后24 h的原位超氧化物生成。缺血前0.5小时用罗布麻素治疗可降低野生型Nox2（-/-）小鼠的总梗死体积、神经功能损伤和死亡率，但对Nox2（-/-）小鼠无效。相反，在再灌注开始后1小时用罗布麻素处理没有保护作用。脑缺血和再灌注在24小时增加了大脑中超氧化物的产生，罗布麻素预处理而不是后处理降低了超氧化物水平。在野生型Nox2（-/-）小鼠缺血前给予罗布麻素改善中风后的预后，但对Nox2（-/-）小鼠无效。
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.