Karatas H, Eun Jung Joo, Lo E H, van Leyen K
Massachusetts General Hospital, Harvard Medical School, Neuroprotecgtion Research Laboratory, Department of Radiology, Charlestown, MA, USA; Hacettepe University, Institute of Neurological Sciences and Psychiatry, Ankara, Turkey.
Massachusetts General Hospital, Harvard Medical School, Neuroprotecgtion Research Laboratory, Department of Radiology, Charlestown, MA, USA.
Brain Res. 2018 Jan 1;1678:123-128. doi: 10.1016/j.brainres.2017.10.024. Epub 2017 Oct 24.
12/15-Lipoxygenase (12/15-LOX) contributes to the brain damage after middle cerebral artery occlusion (MCAO) in the acute phase of stroke. The aim of this study was to investigate the effects of a 12/15-LOX inhibitor, LOXBlock-1(LB1), in mice using a FeCl-induced permanent distal MCAO model and FeCl-induced ischemia/thrombolysis with tPA. In order to induce permanent distal MCAO, 30% FeCl was used in C57BL6 mice. LB1 or DMSO treatments were applied intraperitoneally 2 h following MCAO. For FeCl-induced ischemia/thrombolysis experiments, 10% FeCl was preferred so as to obtain reperfusion with tPA in CD1 mice. 4 h following ischemia either LB1 or DMSO and iv tPA was administered. Outcomes were NSS, weight loss, infarct volume, hemorrhage area and reperfusion rate. FeCl-induced distal MCAO caused an increase in 12/15-LOX signal in the ischemic cortex with an increase in MDA2 and AIF immunoreactivity. LB1 treatment, applied 2 h after ischemia, significantly decreased the infarct volume at 24 h of permanent distal MCAO. Weight loss was also significantly reduced in LB1 treated group. Distal MCAO and tPA application with LB1 or DMSO showed that treatment significantly decreased the infarct volume and the hemorrhage area. The reperfusion rate in the LB1-treated group was surprisingly higher than in the DMSO group and NSS results were significantly improved. These data suggest that LB1 can be used as an adjuvant agent to tPA. This study not only shows the effects of LB1 treatment in distal MCAO but also confirms that FeCl-induced MCAO model can be a useful tool to screen novel treatment options in stroke.
12/15-脂氧合酶（12/15-LOX）在中风急性期大脑中动脉闭塞（MCAO）后导致脑损伤。本研究的目的是使用FeCl3诱导的永久性远端MCAO模型和FeCl3诱导的tPA缺血/溶栓模型，研究12/15-LOX抑制剂LOXBlock-1（LB1）对小鼠的影响。为了诱导永久性远端MCAO，在C57BL6小鼠中使用30%的FeCl3。MCAO后2小时腹腔注射LB1或二甲基亚砜（DMSO）进行处理。对于FeCl3诱导的缺血/溶栓实验，优选使用10%的FeCl3以便在CD1小鼠中实现tPA再灌注。缺血4小时后，给予LB1或DMSO以及静脉注射tPA。观察指标为神经功能缺损评分（NSS）、体重减轻、梗死体积、出血面积和再灌注率。FeCl3诱导的远端MCAO导致缺血皮层中12/15-LOX信号增加，同时丙二醛2（MDA2）和凋亡诱导因子（AIF）免疫反应性增加。缺血后2小时给予LB1处理，在永久性远端MCAO 24小时时显著降低了梗死体积。LB1处理组的体重减轻也显著减少。远端MCAO以及联合LB1或DMSO应用tPA表明，该处理显著降低了梗死体积和出血面积。LB1处理组的再灌注率出奇地高于DMSO组，并且NSS结果显著改善。这些数据表明LB1可作为tPA的辅助药物。本研究不仅显示了LB1处理对远端MCAO的影响，还证实了FeCl3诱导的MCAO模型可作为筛选中风新治疗方案的有用工具。
