A novel mouse model of thromboembolic stroke

Abstract

BackgroundWe previously demonstrated that tissue plasminogen activator (tPA) reduces infarct size after mechanical middle cerebral artery occlusion (MCAO) in wild-type (WT) mice and transgenic mice expressing human leukocyte antigen DR2 (DR2-Tg). Clinically, tPA limits ischemic damage by dissolving the clot blocking blood flow through a cerebral artery. To mimic the clinical situation, we developed a new mouse model of thromboembolic stroke, and tested the efficacy of tPA in WT and DR2-Tg mice.New Method Autologous blood is withdrawn into a PE-8 catheter filled with 2 IU α-thrombin. After exposing the catheter briefly to air, the catheter is reintroduced into the external (ECA) and advanced into the internal carotid artery (ICA) to allow for intravascular injection of thrombin at the MCA bifurcation. To validate the model, we tested the effect of tPA on laser-Doppler perfusion (LDP) over the MCA territory and infarct size in WT and DR2-Tg mice. ResultsThe procedure results in a consistent drop in LDP, and leads to a highly reproducible ischemic lesion. When administered at 15min after thrombosis, tPA restored LDP and resulted in a significant reduction in infarct size at 24h after thrombosis in both WT and DR2-Tg. Comparison with Existing MethodsOur model significantly reduces surgery time, requires a single anesthesia exposure, and produces a consistent and predictable infarction, with low variability and mortality. ConclusionWe validated the efficacy of tPA in restoring blood flow and reducing infarct in a new model of endovascular thromboembolic stroke in the mouse.