Comparison of Large Animal Models for Acute Ischemic Stroke: Which Model to Use?

Abstract

Translation of acute ischemic stroke research to the clinical setting remains limited over the last few decades with only one drug, recombinant tissue-type plasminogen activator, successfully completing the path from experimental study to clinical practice. To improve the selection of experimental treatments before testing in clinical studies, the use of large gyrencephalic animal models of acute ischemic stroke has been recommended. Currently, these models include, among others, dogs, swine, sheep, and nonhuman primates that closely emulate aspects of the human setting of brain ischemia and reperfusion. Species-specific characteristics, such as the cerebrovascular architecture or pathophysiology of thrombotic/ischemic processes, significantly influence the suitability of a model to address specific research questions. In this article, we review key characteristics of the main large animal models used in translational studies of acute ischemic stroke, regarding (1) anatomy and physiology of the cerebral vasculature, including brain morphology, coagulation characteristics, and immune function; (2) ischemic stroke modeling, including vessel occlusion approaches, reproducibility of infarct size, procedural complications, and functional outcome assessment; and (3) implementation aspects, including ethics, logistics, and costs. This review specifically aims to facilitate the selection of the appropriate large animal model for studies on acute ischemic stroke, based on specific research questions and large animal model characteristics.

Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities

“…Large animal stroke models could aid in the selection of the most viable therapies to test in clinical trials . 126 A recent study in swine subjected to stroke via an endovascular approach showed that while gadolinium enhancement on T1-weighted MRIs was marginal at 24 hours, likely the result of restricted access of the contrast agent due to limited perfusion of the ischemic territory, immunoglobulin extravasation into the ischemic territory was elevated both subacutely (24 hours) and chronically (up to 3 months), 127 which is similar to findings from clinical studies showing persisting BBB dysfunction in ischemic stroke. 128,129 Despite the mostly neutral or negative outcomes of clinical trials, there are some positive preliminary findings in ischemic and hemorrhagic stroke for anti-inflammatory treatments, such as with lymphocyte-trapping agent fingolimod, [130][131][132] approved to treat relapsing forms of multiple sclerosis.…”

“…The use of large gyrencephalic animal models, including sheep, dogs, swine, and nonhuman primates, has been recommended by the Stroke Therapy Academic Industry Roundtable to complement the preclinical testing in rodents and enhance the clinical translation of promising cerebroprotective strategies. Large animal stroke models could aid in the selection of the most viable therapies to test in clinical trials 126 . A recent study in swine subjected to stroke via an endovascular approach showed that while gadolinium enhancement on T1-weighted MRIs was marginal at 24 hours, likely the result of restricted access of the contrast agent due to limited perfusion of the ischemic territory, immunoglobulin extravasation into the ischemic territory was elevated both subacutely (24 hours) and chronically (up to 3 months), 127 which is similar to findings from clinical studies showing persisting BBB dysfunction in ischemic stroke.…”

Temporal and sequence-related variability in diffusion-weighted imaging of presumed cerebrovascular accidents in the dog brain

“…Rodent ischemic CVA DWI abnormalities resolve faster than those observed in humans ( 4 , 9 , 31 , 50 ). Dogs and primates are more gyrencephalic, have more gray matter volume, and have a larger proportion of subcortical white matter affected by induced stroke, as compared to rodents ( 50 ). Consistent with previous reports, we show examples of presumed canine CVAs with reduced ADC values up to 5 days after the onset of signs.…”

Microfluidic Model to Evaluate Astrocyte Activation in Penumbral Region following Ischemic Stroke

“…On the other hand, animal models offer a valuable tool, but the animal brain physiology has critical differences compared to the human brain. Additionally, animal models are difficult to monitor on a cellular level and are associated with severe side effects, or even death, posing serious ethical concerns [ 18 ].…”