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

Abstract

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). The comparative effects of microplasmin (microPli) and tPA on ICB were evaluated in a thrombotic middle cerebral artery (MCA) occlusion model in mice. A dose of microPli (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 microPli 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. In controls given solvent at 4 h, ICB was on average 8.8 micro L, which was significantly increased with 10 mg kg(-1) microPli and with 4 and 8 mg kg(-1) tPA to 12-13 micro L (P < 0.05 each vs. controls, n = 7-9), whereas 5 mg kg(-1) microPli did not affect bleeding (8.5 micro L P = NS vs. controls, n = 7). When given at 30 min, neither microPli nor tPA altered ICB (6.3-6.8 micro L, mean; n = 7-9). tPA but not microPli 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) microPli, respectively (n = 10). microPli 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.