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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, AUC 5-110min , was calculated. Results: The CBF(%) decreased after the clot injection, indicating the clot embolized the MCA. A significant increase of the AUC 5-110min 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 AUC 5-110min (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.

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. The objectives of this study were to establish a tissue plasminogen activator (tPA)-sensitive cerebral hemorrhage model and to assess the hemorrhagic risk of DS-1040. Methods: After glucose administration (i.p.), male SHR/Izm rats were subjected to middle cerebral artery occlusion (MCAO) using an intraluminal monofilament. Establishment of tPA-sensitive model: Rats were subjected to MCAO for 1, 2, or 3 h followed by recanalization. tPA (10 mg/kg) or saline (control) was intravenously administered by 10% bolus and 90% infusion just before recanalization. At 2.5 h after recanalization, cerebral hemorrhage was quantified by measuring the excess hemoglobin in the ischemic hemisphere compared to the contralateral side. Hemorrhagic risk assessment: Rats were subjected to MCAO for 3 h followed by recanalization. At 135 min after MCAO, saline (control) and DS-1040 (30 mg/kg) were intravenously injected as bolus. The dosage of DS-1040 was set to achieve full inhibition of TAFIa. As a positive control, tPA (7 mg/kg) was intravenously administered by 10% bolus and 90% infusion at 5 min before recanalization. The excess hemoglobin was determined at 1 h after recanalization. Results: Establishment of tPA-sensitive model: Excess hemoglobin in the tPA group significantly increased in animals subjected to 2 and 3-h MCA occlusion compared to each corresponding control group. Hemorrhagic risk assessment: In the rt-PA group, excess hemoglobin was significantly increased (63.03 ± 8.38 mg/dL, mean ± SE) compared to the control group (38.74 ± 2.10 mg/dL). In contrast, excess hemoglobin in the DS-1040 group was 33.21 ± 3.28 mg/dL. Conclusions: Using hypertensive rats with transient hyperglycemia, we have established a tPA-sensitive cerebral hemorrhage model. DS-1040 did not significantly increase the cerebral hemorrhage compared to the control. These data suggest DS-1040 has the potential to be a thrombolytic enhancer with low risk of cerebral hemorrhage.