In this State-of-the-Art Session entitled, “Neurobiology and Stroke-Stroke Models: Time for a Compromise”, Denis Vivien, M.D., Ph.D. discussed two stroke models being studied in his laboratory. These mouse models are designed to mimic stroke clinically with both fibrin-rich and platelet-rich clots.
- In a model in which thrombin is injected directly into the cerebral artery, Vivien has shown fibrin-rich clot formation, which demonstrates the pathology of stroke and mimics the therapeutic window for tissue plasminogen activator (tPA) intervention.
- In a second model utilizing the local application of FeCl3, he has demonstrated platelet-rich clot formation that has allowed testing of therapeutic agents such as GpIb-alpha inhibitors and n-acetyl cysteine (NAC).
Researchers are able to observe a clinically relevant animal model, test therapeutic strategies, and evaluate response to potential pharmacologic interventions.
Stroke is a common cause of death worldwide; 80% of strokes are ischemic and 20% are hemorrhagic. Current treatments for ischemic stroke include tPA and surgical thrombectomy. There are limitations to these approaches. tPA has a time-limited therapeutic window, hemorrhage is a major risk, and it has the potential to cause neurotoxicity. Successful recanalization rates are relatively low; there is a 2-hour recanalization rate of 21.3%.
New approaches are necessary to improve the treatment of stroke. In the lab, existing preclinical models do not completely recapitulate stroke in the clinical setting.
In the first model discussed, thrombin was injected directly into the middle cerebral artery, which caused an appropriate reduction in arterial flow velocity; clot formation was confirmed by angiography. When timed appropriately, infused tPA successfully lysed the clot and the ischemic lesion reduced, mimicking the clinical scenario. This approach has been adopted by other labs and in a meta-analysis of the cumulative work, this model is highly reproducible. Importantly, this model facilitates investigation of the therapeutic windows for pharmacologic intervention.
Since thrombi which are platelet-rich are resistant to tPA treatment, Vivien developed a second model to assess stroke associated with platelet-rich thrombi by local application of FeCl3. This model allowed investigation of the effects of GpIb-alpha inhibitors. GpIb-alpha inhibitor therapy was shown to improve central blood flow. More recently, he has tested NAC to promote cleavage of von Willebrand factor and improve central blood flow. NAC improved cerebral artery blood flow, suggesting it may help promote clot lysis of platelet-rich clots.
Using these mouse models, human stroke can be mimicked and used to potentially predict clinical response in humans. By using models such as this, clinicians can consider new treatments and combinations of existing drugs.