Animal models of stroke for preclinical drug development: A comparative study of flavonols for cytoprotection

Abstract

Laboratory animals have been used extensively to mimic human ischemic stroke with the aim of discovering drugs that minimize damage and reduce loss of motor and cognitive functions. To date, this has not led to successful clinical translation. Here we consider the available animal models of stroke with discussion focusing on their strengths and limitations for assessing neuroprotective actions. For assessment of drugs outside of thrombolytic therapies, we propose the use of the endothelin-1 (ET-1) model of stroke in conscious animals as a better model than the more common procedure of inducing focal stroke in anesthetized rats with a vascular occluder. The ET-1 model of ischemic stroke allows for stratification of animals to drug trial based on predictive outcomes assessed during stroke induction, mimicking the scenario of stroke patients who are assessed for functional outcome and survival for clinical management and to correctly stratify treatment groups for clinical trials. We highlight the value of applying a predictive outcome score to animals prior to treatment stratification using the water-soluble derivative of the flavonol, 3',4'-dihydroxyflavonol: an effective neuroprotective drug in rats with modest focal strokes but not in rats with severe strokes. Finally, we discuss the use of flavonols