Tissue plasminogen activator deficiency preserves neurological function and protects against murine acute ischemic stroke

•tPA deficiency impeded intracerebral bleeding through reducing MMP-9 activity after acute IS.•Inhibiting tPA-gene expression protected brain function from acute IS injury.•tPA deficiency predicted prognostic outcomes after acute IS.

BackgroundWe tested the hypothesis that tissue plasminogen activator (tPA) deficiency protected against acute ischemic stroke (AIS)-induced brain injury.Methods and ResultsWild-type mice (n = 54) were categorized into group 1 (sham control, n = 18) and group 3 [AIS by permanent ligation of left common carotid artery (CCA) and cramping right CCA for 1 h and then reperfusion followed by hypoxia (11% of oxygen supply for 2 h), n = 36]. Similarly, tPA knockout (tPA−/−) mice (n = 54) were randomized into group 2 (sham control, n = 18) and group 4 (AIS, n = 36). By day 28 after AIS procedure, mortality rate was higher in group 3 (77.8%) than in group 4 (38.9%) and lowest in groups 1 (0%) and 2 (0%) (p < 0.001). By days 3 and 28, MRI demonstrated a pattern of changes in brain-infarct volume identical to that of mortality among four groups (p < 0.001). By day 28, protein expressions of inflammatory (MMP-9, TNF-α, NF-κB, iNOS, PAI-1, RANTES), oxidative (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase-3 & PARP, Bax), and fibrotic (Smad3, TGF-β) biomarkers and cellular expressions of inflammation (CD11, F4/80, GFAP), DNA-damage (γ-H2AX) and brain-edema (AQP4) markers exhibited an identical pattern compared to that of mortality (all p < 0.001), whereas protein expressions of endothelial (eNOS, CD31), anti-fibrotic (Smad1/5, BMP-2) biomarkers, and number of small vessels displayed an opposite pattern (all p < 0.001) among four groups. Expressions of protein and cellular angiogenesis markers (VEGF, SDF-1α, CXCR4) were progressively increased from groups 1 and 2 to group 4 (all p < 0.0001).ConclusiontPA deficiency protected the brain from AIS injury.