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

Abstract

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 mm 3, mean ± SD) than in controls (8.9 ± 5.0 mm 3, P < 0.05) after permanent MCA ligation (plasma PAI-1 level 39 ± 23 ng mL-1 in transgenic mice vs. 1.5 ± 0.6 ng mL-1 in 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-PA gene deficient mice. Conclusions: High PAI-1 levels reduced infarct volume in the permanent MCA ligation model, but enhanced it in the MCA thrombosis model. © 2005 International Society on Thrombosis and Haemostasis.