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.

Keywords: cerebral ischemia; circle of Willis; focal ischemic models; functional assessment tests; neuroprotection; preclinical model.

FIGURE 1

Circle of Willis (CoW) of mammalian stroke models. ACA, anterior cerebral artery; ACoA, anterior communicating artery; BA, basilar artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PCoA, posterior communicating artery; VA, vertebral artery. (Hand drawn using Paint 3D based on the schematic representations in Sorby‐Adams, A. J., Vink, R., & Turner, R. J. (2018). Large animal models of stroke and traumatic brain injury as translational tools. American Journal of Physiology‐Regulatory, Integrative and Comparative Physiology, 315(2), R165‐R190. https://doi.org/10.1152/ajpregu.00163.201