MESSENGER-RNAS ENCODING UROKINASE-TYPE PLASMINOGEN-ACTIVATOR AND PLASMINOGEN-ACTIVATOR INHIBITOR-1 ARE ELEVATED IN THE MOUSE-BRAIN FOLLOWING KAINATE-MEDIATED EXCITATION

Urokinase-type plasminogen activator (uPA) is an inducible extracellul ar serine protease implicated in fibrinolysis and in tissue remodeling . Recently, we have localized uPA mRNA strictly in limbic structures a nd the parietal cortex of the adult mouse brain. Here, we tested wheth er the systemic treatment of mice with kainic acid (KA), an amino acid inducing limbic seizures, could elevate in the brain mRNAs encoding u PA and its specific inhibitor, plasminogen activator inhibitor-1 (PAI- 1), a major antifibrinolytic agent. Brain sections encompassing the hi ppocampus were tested through in situ hybridization using radiolabeled riboprobes specific for the two mRNA species. The results showed that KA greatly enhanced both mRNA species in sites of limbic structures a nd cortex. However, in the hypothalamus and brain blood vessels only P AI-1 mRNA was elevated. Those were also the only two locations where P AI-1 mRNA was detected in the non-treated control brain, although at a low level. For both mRNAs, KA enhancement was first evident 2-4 h aft er treatment, and it was most prolonged in the hippocampal area, where prominent hybridization signals persisted for three days. Here, both mRNAs were initially elevated in the hilar region of the dentate gyrus and in the molecular and oriens layers; however, PAI-1 mRNA became ev ident throughout the area, while uPA mRNA became especially pronounced in the CA3/CA4 subfield. In the cortex both mRNA types were induced, but only uPA mRNA was elevated in the retrosplenial cortex, and also i n the subiculum. In the amygdaloid complex, uPA mRNA was restricted to the basolateral nucleus, whereas PAI-1 mRNA was seen throughout the s tructure, however, excluding this nucleus. These data show that seizur e activity enhances the expression of uPA and PAI-1 genes in the brain ; the patterns of enhancement suggest that the protease and its inhibi tor may act in brain plasticity in synchrony, however, also independen tly of each other. Furthermore, the results suggest that by elevating PAI-1 mRNA in brain blood vessels, limbic seizures generate a risk for stroke.