Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization.
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 alpha(2)-antiplasmin (alpha(2)-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 alpha(2)-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 microL (range, 20-34) (n = 10) with saline and 23 microL (range, 17-26) (n = 9) with a single bolus of 0.07 mg Pli, given after MCA ligation (P =.010), which reduced alpha(2)-AP to 44% and fibrinogen from 0.75 to 0.44 g/L. FII was 20 microL (range, 13-26) (n = 6, P =.025) with 0.2 mg mPli and was 24 microL (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 alpha(2)-AP and fibrinogen and reduced FII at 24 hours from 20 microL (range, 9.9-38) (n = 6) to 7.0 microL (range, 0.44-31) (n = 7, P =.032). Thus, reduction of circulating alpha(2)-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 alpha(2)-AP might reduce ischemic stroke in the absence of reperfusion.
Nagai
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N
Center for Molecular and Vascular Biology and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
De Mol
M
M
Van Hoef
B
B
Verstreken
M
M
Collen
D
D
D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006224:Cricetinae; D005340:Fibrinogen / Q000032:analysis; D005341:Fibrinolysin / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007797:Laminin / Q000032:analysis; D008026:Ligation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000601:surgery; D000979:alpha-2-Antiplasmin / Q000032:analysis* / Q000276:immunology
D007140:Immunoglobulin Fab Fragments; D007797:Laminin; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D005341:Fibrinolysin