Neurovascular protection by ischemic tolerance: Role of nitric oxide and reactive oxygen species
Neurovascular protection by ischemic tolerance: Role of nitric oxide and reactive oxygen species
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DOI：
10.1523/jneurosci.1645-07.2007
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发表时间：
2007-07-04
影响因子：
5.3
通讯作者：
Iadecola, Costantino
中科院分区：
文献类型：
--
作者：
Kunz, Alexander;Park, Laibaik;Iadecola, Costantino
脑缺血预处理或耐受是一种强大的神经保护现象，亚致死性伤害性刺激使大脑对随后的破坏性缺血性损伤具有抵抗力。我们在大脑中动脉闭塞（MCAO）小鼠模型中使用脂多糖（LPS）作为预处理刺激物，以检查脑血管功能的改善是否有助于保护作用。 MCAO 前 24 小时注射 LPS 可将梗死率减少 68%，并将未发生梗塞的大脑区域的缺血性脑血流量 (CBF) 改善 114%。此外，LPS 可以防止 MCAO 引起的脑血管调节功能障碍，神经活动、高碳酸血症或内皮依赖性血管舒张剂乙酰胆碱产生的 CBF 增加正常化就证明了这一点。在缺乏诱导型一氧化氮合酶 (iNOS) 或超氧化物生成酶 NADPH 氧化酶的 nox2 亚基的小鼠中，没有观察到 LPS 的这些有益作用。 LPS 增加了野生型小鼠中的活性氧和过氧亚硝酸盐标记物 3-硝基酪氨酸，但在 nox2 null 小鼠中则没有。过氧亚硝酸盐分解催化剂 5,10,15,20-四(4-磺基苯基)卟啉铁 (III) 减弱了 LPS 诱导的硝化作用，并抵消了 LPS 对梗塞体积、缺血性 CBF 和血管反应性的有益作用。因此，LPS 可以保留神经血管功能并改善有梗塞风险的缺血区域区域的 CBF。这种效应是由 iNOS 衍生的 NO 和 nox2 衍生的超氧化物形成的过氧亚硝酸盐介导的。数据表明，保存脑血管功能是缺血耐受的重要组成部分，并表明将神经保护和血管保护相结合可能是治疗缺血性脑损伤的有价值的策略。
Cerebral ischemic preconditioning or tolerance is a powerful neuroprotective phenomenon by which a sublethal injurious stimulus renders the brain resistant to a subsequent damaging ischemic insult. We used lipopolysaccharide (LPS) as a preconditioning stimulus in a mouse model of middle cerebral artery occlusion (MCAO) to examine whether improvements in cerebrovascular function contribute to the protective effect. Administration of LPS 24 h before MCAO reduced the infarct by 68% and improved ischemic cerebral blood flow (CBF) by 114% in brain areas spared from infarction. In addition, LPS prevented the dysfunction in cerebrovascular regulation induced by MCAO, as demonstrated by normalization of the increase in CBF produced by neural activity, hypercapnia, or by the endothelium-dependent vasodilator acetylcholine. These beneficial effects of LPS were not observed in mice lacking inducible nitric oxide synthase (iNOS) or the nox2 subunit of the superoxide-producing enzyme NADPH oxidase. LPS increased reactive oxygen species and the peroxynitrite marker 3-nitrotyrosine in wild- type mice but not in nox2 nulls. The peroxynitrite decomposition catalyst 5,10,15,20-tetrakis( 4-sulfonatophenyl) porphyrinato iron (III) attenuated LPS-induced nitration and counteracted the beneficial effects of LPS on infarct volume, ischemic CBF, and vascular reactivity. Thus, LPS preserves neurovascular function and ameliorates CBF in regions of the ischemic territory at risk for infarction. This effect is mediated by peroxynitrite formed from iNOS-derived NO and nox2-derived superoxide. The data indicate that preservation of cerebrovascular function is an essential component of ischemic tolerance and suggest that combining neuroprotection and vasoprotection may be a valuable strategy for treating ischemic brain injury.