Abstract Body: Introduction: In 2007, Orset et al. proposed an innovative thromboembolic stroke model in mice where murine thrombin is injected into the M2 segment of the middle cerebral artery (MCA) to induce arterial thrombosis. It emerged as a sensitive but versatile and translationally tool for evaluating pharmacological efficacy and safety of innovative drugs. After 7 years of use in our hands, we aggregate the data from a large panel of studies.
Hypothesis: The Thromboembolic stroke model accurately mimics clinical stroke scenarios, providing a reliable platform for assessing drug efficacy and safety.
Methods: We evaluated pharmacological efficacy of Alteplase and Tenecteplase in the thrombin stroke model and determined Alteplase therapeutic window. We compared the effects of Alteplase in thrombin-model with FeCl3-induced thrombosis model. The studies included various mouse strains (OF1 and C57BL/6), assessing the impact of diabetes and hypertension and sex-dependent responses on treatment outcomes. Safety aspects included drug interaction with reference drugs and hemorrhagic transformation (HT) rate and severity evaluation.
Results: Both Alteplase and Tenecteplase significantly improve MCA recanalization and reduced lesion volume in the thrombin model as measured by MRI, with efficacy diminishing after 20 minutes, and no visible effects by 90 min post-stroke. Male and female mice exhibited similar response to treatment in healthy and comorbid animals. However, Alteplase showed efficacy only in OF1 mice. The FeCl3 model showed no response to Alteplase, highlighting its utility in mimicking patient subgroups with fibrinolysis resistant profiles. In the presence of comorbidities, lesion volume and HT were increased and Alteplase was ineffective. The combination of other drugs with Alteplase demonstrated additional benefits in reducing lesion volume, demonstrating that the model allows for superiority study, but also highlighted potential safety concerns.
Conclusions: The thrombin stroke model in mice is a robust system for the translational evaluation of therapeutic agents, providing key insights into both efficacy and safety of tested drugs. Its ability to simulate several clinical scenarios, including patient comorbidities and drug interactions, positions it as a relevant model for stroke preclinical studies.