Comparative effects of microplasmin and tissue-type plasminogen activator (tPA) on cerebral hemorrhage in a middle cerebral artery occlusion model in mice

Background: Thrombolytic therapy of ischemic stroke with tissue-type plasminogen activator (tPA) improves clinical outcome which may, however, be partially offset by significant intracerebral bleeding (ICB). Objects: The comparative effects of microplasmin (muPli) and tPA on ICB were evaluated in a thrombotic middle cerebral artery (MCA) occlusion model in mice. Methods: A dose of muPli (5 mg kg(-1)) or tPA (4 mg kg(-1)) which are comparably effective for reduction of brain damage, or a double dose (10 or 8 mg kg(-1) respectively) or the muPli excipient as a control were intravenously administered as a bolus at 30 min or 4 h after MCA occlusion. ICB was measured at 24 h by hemoglobin assay of exsanguinated brain extracts. Bleeding time was measured by tail cutting. Results: In controls given solvent at 4 h, ICB was on average 8.8 muL, which was significantly increased with 10 mg kg(-1) muPli and with 4 and 8 mg kg(-1) tPA to 12-13 muL (P < 0.05 each vs. controls, n = 7-9), whereas 5 mg kg(-1) muPli did not affect bleeding (8.5 muL P = NS vs. controls, n = 7). When given at 30 min, neither muPli nor tPA altered ICB (6.3-6.8 muL, mean; n = 7-9). tPA but not muPli increased bleeding time; from 2.4 min in controls to 5.9 min (median, P < 0.05 vs. controls) and 8.7 min (P < 0.01 vs. controls) with 4 and 8 mg kg(-1), respectively, and to 2.3 and 2.9 min with 5 and 10 mg kg(-1) muPli, respectively (n = 10). Conclusions: muPli at a dose comparably effective as tPA for brain damage reduction induced significantly less ICB, and less bleeding time prolongation in mice with thrombotic MCA occlusion.