Abstract TP271: Improvement of Cerebral Blood Flow With DS-1040 in a Rat Thromboembolic Stroke Model
Introduction: DS-1040 is a novel inhibitor of the activated thrombin-activatable fibrinolysis inhibitor (TAFIa) and is in clinical development for the treatment of acute ischemic stroke (AIS). The objective of this study was to investigate the effect of DS-1040 on cerebral blood flow (CBF) in a rat thromboembolic stroke model.
Methods: The CBF was transcranially and continuously monitored during the experiment by laser Doppler flowmetry system using a probe fixed to the skull above the territory of the right middle cerebral artery (MCA) of an anesthetized male SHR/Izm rat. After recording basal CBF, non-autologous whole blood clot was injected into the internal carotid artery. We conducted a 3-arm study. Saline (control) and DS-1040 (3.0 mg/kg) were intravenously injected as a bolus 5 min after the clot injection. The dosage of DS-1040 was set to achieve full inhibition of TAFIa during the experiment. Recombinant tissue plasminogen activator (rt-PA, 7.0 mg/kg; positive control) was intravenously injected 5 min after the clot injection by 10% bolus and 90% infusion for 60 min. The CBF(%) was defined as percent of the CBF at each time point to the mean basal CBF and the area under the curve of the CBF(%) after the drug injection, AUC5-110min, was calculated.
Results: The CBF(%) decreased after the clot injection, indicating the clot embolized the MCA. A significant increase of the AUC5-110min was observed in the rt-PA group (8416.2 %·min ± 642.4 %·min, mean ± SE) compared to the control group (3728.7 %·min ± 684.2 %·min), indicating the model is sensitive to tPA. DS-1040 also significantly increased the AUC5-110min (6645.3 %·min ± 861.9 %·min) compared to the control group.
Conclusions: DS-1040 restored CBF in a rat thromboembolic stroke model suggesting DS-1040 is expected to be beneficial for the treatment of patients with acute ischemic stroke. To the authors’ knowledge, this is the first report of an inhibitor of TAFIa improving the CBF in a thromboembolic stroke model.
Author Disclosures: K. Noguchi: Employment; Significant; Daiichi Sankyo Co., Ltd. N. Edo: Employment; Significant; Daiichi Sankyo Co., Ltd. Y. Ito: Employment; Significant; Daiichi Sankyo Co., Ltd. Y. Morishima: Employment; Significant; Daiichi Sankyo Co., Ltd. K. Yamaguchi: Employment; Significant; Daiichi Sankyo Co., Ltd..
- © 2016 by American Heart Association, Inc.