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    • The current study was designed to

    2023-11-17

    The current study was designed to investigate the effects of the 12/15-LOX inhibitor, LOXBlock-1 (LB1) in mice using a FeCl3-induced distal MCAO model, and to test its utility in conjunction with subsequent thrombolysis with tPA, which is to date the only FDA-approved drug for acute stroke treatment. This study will help us to improve our knowledge about the effect of LB-1 in different models of stroke other than previously used reperfusion models.
    Results
    Discussion Within this study, as proven using the immunohistochemical methods, we have demonstrated that lipoxygenase activation has a vital contribution in the pathophysiology of ischemia in the FeCl3-induced distal MCAO model. Previously, Khanna et al. (Khanna et al., 2005, Park et al., 2011) and our group have reported the involvement of 12/15-LOX in proximal MCAO models (Jin et al., 2008, van Leyen et al., 2006, Yigitkanli et al., 2013). However, considering a distal MCAO model, this is the first report demonstrating an increased LOX immunoreactivity in the ischemic 57 9 and in the peri-infarct area. This immunoreactivity was colocalized with an oxidative stress marker, malondialdehyde (MDA2) (Fig. 1A–C). Malondialdehyde is a breakdown product formed by the oxidation of arachidonic acid. Increased LOX immunoreactivity was also coincidental with the AIF immunopositivity in the peri-infarct area (Fig. 1J–L). AIF is known to be increased following ischemia (Zhao et al., 2004), and the staining pattern closely resembles what we have found in our previously published data, where 12/15-LOX and AIF were both increased in the peri-infarct region (Pallast et al., 2010). This immunoreactivity was also found in human stroke patients in the peri-infarct area (Yigitkanli et al., 2013). Consistent with a damaging role for increased 12/15-LOX activity in stroke, systemic administration of the 12/15-LOX inhibitor, LB1, 2 h after permanent focal cerebral ischemia significantly reduced infarct size 24 h after the ischemia, and the treatment group demonstrated improved behavioral and health parameters. Finally, we investigated the effects of a combination therapy of lipoxygenase inhibitor with tPA in FeCl3-induced transient ischemia-reperfusion model. LB1 treatment applied 4 h after ischemia onset which was followed by thrombolysis with tPA, significantly decreased infarct volume and hemorrhage area accompanying with better NSS results and reduced weight loss. It might demonstrate that 12/15-LOX inhibition provides benefits when coadministered with tPA after stroke. Yigitkanli et al. also supports our results with the data made 2 h after ischemia onset in filament-induced proximal MCAO model (Yigitkanli et al., 2013). It was previously shown that application of intraperitoneal LB1 treatment either 2, 4 or 6 h after filament-induced focal cerebral ischemia decreased infarct volume (Yigitkanli et al., 2013), and our results here suggest a similar time window for this distal model. In this study it was shown that lipoxygenase activity contributes to the stroke pathophysiology and inhibition of this activity decreases infarct volume in acute distal MCA ischemia model. This study and previous studies also showed that lipoxygenase inhibitors are safe against hemorrhage after stroke when administered alone or even with tPA treatment (Liu et al., 2017, Yigitkanli et al., 2013). This safe time window is 4 h after stroke yet we did not investigate the effects beyond this time window. In addition, inhibition of 12/15-LOX activity strengthens the effect of tPA in accordance with decreased infarct volume and better NSS results. This effect might result from the decrease in the blood-brain barrier permeability through application of the 12/15 LOX inhibitor after stroke (Jin et al., 2008). Recently it was shown that not only tPA-induced hemorrhage, but also warfarin-associated hemorrhagic transformation was significantly reduced using a novel lipoxygenase inhibitor with and without tPA administration (Liu et al., 2017). These results show that 12/15-LOX inhibitors may be a good option to prevent thrombolysis-induced side effects of acute stroke treatment. Also these inhibitors might be used in human acute stroke patients without tPA in the ambulance as it is safe against hemorrhage and effectively decreases infarct volume.