Abstract TP274: Inactivation of Serpinf2 Saves Lives, Prevents Disability and Hemorrhage in Experimental Thromboembolic Ischemic Stroke
More than 15 million individuals suffer ischemic stroke each year. High levels of serpinf2 (Sf2, a2-plasmin inhibitor, a2-antiplasmin) have been identified as a potential risk factor for human ischemic stroke.
Methods: We examined the integrated effects of sf2 in a thromboembolic MCA stroke model with translational relevance to human disease. Using a blinded observer, neuronal cell death was quantified by TTC staining; hemorrhage and brain swelling were determined by planimetry. Immunohistochemistry was used to assess apoptosis, matrix metalloproteinase 9 expression and breakdown of the blood brain barrier.
Results: Increasing the levels of sf2 caused larger infarctions by comparison to control mice (51% larger, p<0.002). Sf2 administration also markedly worsened brain swelling (p<0.05) but it did not cause hemorrhage. Conversely, when mice were given an sf2 inactivator (sf2-i), it markedly reduced stroke infarct size (95%) by comparison to control (p<0.001) and TPA-treated mice (p<0.001). Treatment of mice with an sf2-I also markedly reduced mortality rates by comparison to TPA-treated mice (p<0.0005) or control mice (p<0.004). The survival effect was dose-dependent: lower doses of the sf2-I were less effective than higher doses (p≤ 0.05) but still reduced mortality by comparison to control and TPA (p≤ 0.01). Microscopic examination of the brains of mice surviving the initial stroke period (> 12 hrs.) showed that sf2-i reduced stroke infarct size by comparison to control mice or TPA treated mice (p<0.001). There was less hemorrhage in sf2-i treated mice than occurred in control mice (p<0.001) or than in those receiving TPA (p<0.01). Inactivation of sf2 markedly reduced brain swelling by comparison to controls (p<0.001) and TPA-treated mice (p<0.05). Sf2-i treated mice showed no significant disability in Rotarod behavioral testing when compared to sham mice without strokes.
Conclusions: Sf2 significantly enhances brain injury in ischemic stroke. Since inactivation of Sf2 prevents disability, hemorrhage and death it may prove to be a safe and effective strategy for treating acute ischemic stroke.
- © 2012 by American Heart Association, Inc.