Effects of plasminogen activator inhibitor‐1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice

Background and Objectives: Tissue plasminogen activator (t‐PA) improves the outcome of ischemic stroke by recanalization of occluded vessels, but has neurotoxic side effects in experimental stroke models. Here, the effect of plasminogen activator inhibitor‐1 (PAI‐1), an endogenous inhibitor of t‐PA, on ischemic infarct volume was studied. Methods: After either permanent ligation or thrombotic occlusion of the middle cerebral artery (MCA), infarct volume, spontaneous reperfusion of thrombosed MCA, t‐PA/PAI‐1 complex level, and blood–brain barrier (BBB) permeability in the ischemic region was studied in transgenic mice with overexpression of PAI‐1 and wild‐type littermate controls and in mice with intracerebroventricular injection of human PAI‐1. Results: Infarct volume was smaller in PAI‐1 transgenic mice (2.9 ± 3.7 mm3, mean ± SD) than in controls (8.9 ± 5.0 mm3, P < 0.05) after permanent MCA ligation (plasma PAI‐1 level 39 ± 23 ng mL−1in transgenic mice vs. 1.5 ± 0.6 ng mL−1in controls), whereas after MCA thrombosis it was larger in transgenics (13.1 ± 3.1 mm3) than in controls (8.0 ± 3.2 mm3, P < 0.05). Spontaneous reperfusion of the thrombosed MCA was significantly delayed in transgenic vs. control mice. In the ligation model, t‐PA/PAI‐1 complex levels were higher and BBB disruption was more pronounced in the ischemic region. Human PAI‐1 injection reduced infarct volume by about 50% in wild‐type mice but not in t‐PAgene deficient mice. Conclusions: High PAI‐1 levels reduced infarct volume in the permanent MCA ligation model, but enhanced it in the MCA thrombosis model.