Role of endogenous tissue-type plasminogen activator (tPA) on focal cerebral ischemic injury (FII) after middle cerebral artery occlusion (MCAo) was studied by using tPA deficient mice (KO) and wild type mice (WT). FII size in KO was smaller than that in WT in permanent MCAo whereas larger in transient MCAo. These findings suggest that endogenous tPA protected FII through its thrombolytic action on transient MCAo, but deteriorated by neurotoxicity of tPA on persistent occlusion. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We demonstrated that heparin administration after the MCAo caused cerebral hemorrhage in WT, but not in KO. We observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. We also investigated about hemorrhage induced by tPA administration using MMP3 deficient mouse. The hemorrhage is induced by tPA in wild type mice, but not in MMP3 deficient mice. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation and that hemorrhage induced by tPA administration is related with MMP3.
