Brain edema plays an important role in the secondary brain injury following intracerebral hemorrhage (ICH). Edema formation after ICH has been linked to thrombin toxicity. Therefore, the induction of endogenous serine protease inhibitors, which inhibit thrombin prior to ICH may limit edema formation. This study examines whether injection of a low dose of thrombin upregulates such inhibitors and induces tolerance to subsequent ICH. Rats received intracerebral infusions of either one unit thrombin or saline into the right caudate nucleus. After seven days, the rats were either (A) used to examine colligin (a serine protease inhibitor) induction by Western blot analysis, immunohistochemistry and immunofluorescent double labeling, (B) to determine brain water content, or (C) they received a second injection of 50 microL blood and brain edema was determined one day later. Intracerebral infusion of thrombin caused a marked upregulation of colligin, a serine protease inhibitor, in the ipsilateral basal ganglia. Immunocytochemistry and immunofluorescent double labeling showed that colligin was induced in astrocytes. Infusion of this dose of thrombin alone did not affect brain water content but it significantly attenuated subsequent ICH-induced brain edema (79.0 +/- 0.5 vs. 81.4 +/- 0.9%, P < 0.01). Our results demonstrate that low doses of thrombin upregulate brain colligin levels and attenuate edema formation induced by ICH.