[Role of endogenous tPA in stroke]

The role of endogenous tissue-type plasminogen activator (tPA) on focal cerebral ischemic injury (FII) after middle cerebral artery (MCA) occlusion was studied by using tPA gene deficient (KO) mice and wild type (WT) mice. MCA was occluded by thrombosis induced by 3 different intensities of photochemical damage of MCA. FII size in KO mice was smaller than in WT mice in mild damage whereas it was larger in severe damage. These results suggested that endogenous tPA protected FII through its thrombolytic action on transient occlusion with mild damage, but deteriorated on persistent occlusion with severe damage. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We investigated the roles of endogenous tPA and MMPs in hemorrhagic cerebral infarction associated with heparin. We demonstrated that heparin administration caused cerebral hemorrhage in WT but not in KO. Heparin administration increased tPA activity and its mRNA expression in WT. We also observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation.