Abstract
Background: Focal cerebral ischemia is characterized by prompt cessation of perfusion by vascular occlusion and delayed microclot formation as a result of hypoxic induction of procoagulatory pathways. Therefore, research efforts focus primarily on lysis of clots and rescuing the ischemic penumbra. Recent data indicate that fibrinolytic pathways are suppressed following cerebral ischemia. Plasminogen activator inhibitors (PAI) are the primary regulators of the fibrinolytic system and modulate clot stability by inhibiting urokinase and tissue type plasminogen activators (uPA / tPA). uPA and tPA cleave plasminogen to plasmin which finally degrades fibrin of formed clots. Suppression of endogenous lysis of micro embolism or spontaneous clot formation might contribute to brain damage following cerebral ischemia. This study therefore investigated the role of PAI in an experimental stroke model by use of PAI-1 and PAI-2 deficient mice. Methods: Brain ischemia was induced for 60 min by temporary filament occlusion of the middle cerebral artery (tMCAO). PAI-1-/-, PAI-2-/-, and wild-type (WT; PAI-1+/+; PAI-2+/+) mice were randomized to tMCAO (n = 10 each group) or sham surgery (n = 4 each group). Brain lesion was quantified 24 h after reperfusion in 2,3,5-triphenyltetrazolium chloride (TTC)-stained sections. Results: In PAI-1-/- mice lesion volume was significantly lower, while infarct size of PAI-2-/- mice was not different compared to WT animals (PAI-1-/-: *34 ± 10 %; PAI-2-/-: 48 ± 13 %; WT: 51 ± 11 %; *P < 0.05 vs. WT). Conclusion: Although both PAI-1 and PAI-2 are up-regulated following stroke, only PAI-1 deficiency demonstrated protection. The data therefore indicate a PAI-1 dependent impairment of the thrombolytic tPA / uPA function following tMCAO. The present study suggests that PAI-1 inhibition might be a promising therapeutic strategy to limit secondary brain damage after ischemic stroke.
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