Preclinical animal studies in ischemic stroke: Challenges and some solutions

Abstract

Despite the impressive efficacies demonstrated in preclinical research, hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotection for ischemic stroke in human clinical trials. Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke. This review recapitulates the available cerebral ischemia animal models, provides an anatomical comparison of the circle of Willis of each species, and describes the functional assessment tests used in these ischemic stroke models. The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored. Innovative animal models more closely resembling human strokes, better techniques in functional outcome assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients. This may involve use of newer molecules or revisiting earlier studies with new experimental designs. Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.

Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

“…The most common gyrencephalic (i.e., possessing a cerebral cortex with convolutions) non-human primates used for modeling ischemic stroke are the Papio and Macaca species of marmoset [145]. Common approaches for inducing an infarct in non-human primates include craniotomy with electrocoagulation, pterional craniotomy, transorbital approaches, or embolization [146]. A recently developed technique involving endovascular transient occlusion of the middle cerebral artery (MCA) with PET-MRI and neuro-functional assessment has been reported to successfully induce focal cerebral ischemia in Macaca fascicularis [147].…”

“…Macaca mullata has the presence of a single distal anterior cerebral artery, thereby in direct contrast with human anatomy [149]. Other limitations of using non-human primates to model cerebral ischemia include the high cost of husbandry and the need for specialized surgical equipment and post-operative recovery requirements [146].…”

“…Common differences may include occlusion time, which typically ranges from 30-120 min transient (tMCAO) or permanent (pMCAO) occlusions [162]. The MCAO model yields reproducible infarct volumes that possess both an ischemic core and penumbra [146]. As such, this is a suitable model for neuroprotection research and is often utilized in the study of BBB damage and repair.…”

“…Specifically, this method can cause a greater degree of cerebral injury as compared to what is normally observed in ischemic stroke. For example, there have been reports in the MCAO model in which cerebral infarctions have extended into the hippocampus, substantia nigra, and thalamus [146]. Likewise, it has been shown that 60 min filamentous MCAO (fMCAO) with reperfusion can lead to retinal cell death; however, visual disturbances have been reported with stroke in humans so this retinal injury from tMCAO may be beneficial for those interested in studying retinal damage in patients [168].…”

Ischemic Stroke, Glucocorticoids, and Remote Hippocampal Damage: A Translational Outlook and Implications for Modeling

“…This disappointment is certainly related to an incomplete current picture of IS pathophysiology. Lack of valid and powerful animal models for human IS is regarded as a major reason for the failure to develop effective neuroprotective drugs ( Narayan et al, 2021 ; Singh et al, 2021 ). Many authors point at this translational failure in IS treatment and note the urgent need to reorganize the design of stroke experimental setups.…”