Depletion of circulating α2-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization

Author:

Nagai Nobus1,De Mol Maria1,Van Hoef Berthe1,Verstreken Maria1,Collen Désiré1

Affiliation:

1. From the Center for Molecular and Vascular Biology and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.

Abstract

Abstract In the absence of arterial recanalization, thrombolytic agents induce a dose-related extension of focal cerebral ischemic injury (FII) in experimental animals. However, FII is smaller in mice lacking α2-antiplasmin (α2-AP), the physiologic inhibitor of plasmin, suggesting its depletion might reduce FII in the absence of reperfusion. Therefore, the effect of human plasmin (Pli), human miniplasmin (mPli), and an Fab fragment neutralizing murine α2-AP (Fab-4H9) on FII after middle cerebral artery (MCA) ligation was studied in mice and in hamsters. In BALB/c mice, the median FII after 24 hours was 28 μL (range, 20-34) (n = 10) with saline and 23 μL (range, 17-26) (n = 9) with a single bolus of 0.07 mg Pli, given after MCA ligation (P = .010), which reduced α2-AP to 44% and fibrinogen from 0.75 to 0.44 g/L. FII was 20 μL (range, 13-26) (n = 6, P = .025) with 0.2 mg mPli and was 24 μL (range, 20-27) (n = 6,P = .020) with 1.7 mg Fab-4H9. Neuronal atrophy and reduction of laminin immunoreactivity were comparably observed in the infarct area after saline and Pli. In hamsters, a single bolus injection of 1 mg Pli, after MCA ligation, depleted α2-AP and fibrinogen and reduced FII at 24 hours from 20 μL (range, 9.9-38) (n = 6) to 7.0 μL (range, 0.44-31) (n = 7,P = .032). Thus, reduction of circulating α2-AP, with a single bolus of plasmin or of a neutralizing antibody fragment, significantly reduced FII after MCA ligation in mouse and hamster models, suggesting that, provided these observations can be extrapolated to human beings, transient depletion of circulating α2-AP might reduce ischemic stroke in the absence of reperfusion.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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