In vivo animal stroke models: a rationale for rodent and non-human primate models

Abstract

On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Approximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke.

Keywords: animals; basic research; cerebral ischemia; clinical application; translational.

Figure 1. Translational Step-Wise Experimental Design for Stroke Neurotherapeutics

Based on STAIR and STEPS criteria, preclinical experimental designs should emphasize the need to demonstrate safety and efficacy of novel therapeutics in clinically relevant animal models. Small animal models should optimize the dose, timing, and route of delivery of therapeutics by using standardized and validated functional outcomes involving behavioral and histological endpoints that are able to capture stroke symptoms with clinical predictive value. To date, most stroke models have not incorporated co-morbidity factors, such as diabetes and hypertension, and their inclusion to testing novel therapeutics will be important to bolster clinical relevance. Recent guidance from the FDA has also indicated the need to better reveal mechanisms of action, as well as imaging of the therapeutics and the stroke brain. In case questions remained unanswered in small animal models (e.g., white matter injury in humans cannot be fully replicated in rodents), the need to explore large animal models, such as NHPs, will further reveal safety and efficacy of the novel therapeutics. In summary, these preclinical studies should be geared towards the successful translation of the envisioned product from the laboratory to the clinic.