Forghani Reza, Kim Hyeon Ju, Wojtkiewicz Gregory R, Bure Lionel, Wu Yue, Hayase Makoto, Wei Ying, Zheng Yi, Moskowitz Michael A, Chen John W
1] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Cereb Blood Flow Metab. 2015 Mar;35(3):485-93. doi: 10.1038/jcbfm.2014.222. Epub 2014 Dec 17.
Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.
除超急性期外，几乎没有有效的中风治疗方案。自由基生成和髓过氧化物酶（MPO）与中风有关。我们研究了这种高氧化酶的药物性降低或基因缺失是否能减少梗死扩展并改善短暂性大脑中动脉闭塞小鼠模型（MCAO）的预后。小鼠用4-氨基苯甲酸酰肼（ABAH）治疗，ABAH是一种特异性不可逆MPO抑制剂。使用了三种治疗方案：（1）在整个21天观察期内每日给药，（2）在急性期（最初24小时）给药，或（3）在亚急性期（从第2天开始每日给药）。我们发现缺血后3至21天同侧大脑中MPO活性升高。4-氨基苯甲酸酰肼使酶活性降低30%至40%，最终梗死体积降低60%（P<0.01）。接受MCAO的MPO基因敲除（KO）小鼠的最终梗死体积也有类似程度的减小（P<0.01）。ABAH治疗组或MPO-KO小鼠的神经行为预后（P<0.001）和存活率（P=0.01）也得到改善，但ABAH对MPO-KO小鼠没有额外的有益作用，证实了ABAH的特异性。有趣的是，在亚急性期抑制MPO活性概括了持续抑制MPO的大部分治疗益处，这表明在中风发作24小时后给予靶向MPO的治疗可能是有用的。
