Inhibiting 12/15-lipoxygenase to treat acute stroke in permanent and tPA induced thrombolysis models

摘要

Highlights ? Lipoxygenase activity contributes to the stroke pathophysiology. ? Inhibition of this activity decreases infarct volume in acute distal MCA ischemia model. ? Inhibition of 12/15-LOX activity strengthens the effect of tPA. ? This is in accordance with decreased infarct volume and better NSS results. ? FeCl 3 -induced distal MCAO model is useful to screen novel drugs for acute stroke treatment with or without thrombolysis. Abstract 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 3 -induced permanent distal MCAO model and FeCl 3 -induced ischemia/thrombolysis with tPA. In order to induce permanent distal MCAO, 30% FeCl 3 was used in C57BL6 mice. LB1 or DMSO treatments were applied intraperitoneally 2?h following MCAO. For FeCl 3 -induced ischemia/thrombolysis experiments, 10% FeCl 3 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 3 -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 3 -induced MCAO model can be a useful tool to screen novel treatment options in stroke.