Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model - Studies in tPA-deficient mice and wild-type mice on a matched genetic background

Although the serine protease, tissue plasminogen activator (tPA), is approv ed by the US Food and Drug Administration for therapy to combat focal cereb ral infarction, the basic concept of thrombolytic tPA therapy for stroke wa s challenged by recent studies that used genetically manipulated tPA-defici ent (tPA-/-) mice, which suggested that tPA mediates ischemic neuronal dama ge. However, those studies were potentially flawed because the genotypes of tPA-/- and wild-type control mice were not entirely clear, and ischemic ne uronal injury was evaluated in isolation of tPA effects on brain thrombosis . Using mice with appropriate genetic backgrounds and a middle cerebral art ery occlusion stroke model with nonsiliconized thread, which does lead to m icrovascular thrombus formation, in the present study we determined the ris k for cerebrovascular thrombosis and neuronal injury in tPA-/- and genetica lly matched tPA+/+ mice subjected to transient focal ischemia, Cerebrovascu lar fibrin deposition and the infarction volume were increased by 8.2- and 6.7-fold in tPA-/- versus tPA+/+ mice, respectively, and these variables we re correlated with reduced cerebral blood flow up to 58% (P<0.05) and impai red motor neurological score by 70% (P<0.05). Our findings indicate that tP A deficiency exacerbates ischemia-induced cerebrovascular thrombosis and th at endogenous tPA protects the brain from an ischemic insult, presumably th rough its thrombolytic action. In addition, our study emphasizes the import ance of appropriate genetic controls in murine stroke research.