Modeling Risk Factors and Confounding Effects in Stroke
Most research to date has used experimental models in rodents which fail to mimic the underlying causes of stroke in patients or the primary confounding factors. Available data indicate that factors such as atherosclerosis, hypertension, obesity, diabetes
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1. Introduction Animals have been used successfully to study the underlying mechanisms of diverse diseases and to successfully develop new treatments. In many cases, the diseases in question are induced through a means which differs significantly from the clinical course and causes (e.g., implanted tumors in young and otherwise healthy animals) mechanical or pharmacological induction of hypertension and cardiac disease, and pharmacological induction of diabetes. Some have used spontaneous mutations that result in the disease of interest (e.g., genetically obese animals), mutagenesis to cause a pathology (e.g., deafness), or specific genetic manipulation to induce disease (e.g., to cause mutations known to occur in Alzheimer’s). All of these have been very helpful in understanding disease pathology and in the development and testing of new medicines. The situation in experimental studies on stroke is quite different because the animal models we have used have revealed much knowledge of underlying pathological mechanisms, but have (with the notable exception of tPA) failed to deliver new medicines. Ulrich Dirnagl (ed.), Rodent Models of Stroke, Neuromethods, vol. 47, DOI 10.1007/978-1-60761-750-1_9, © Springer Science+Business Media, LLC 2010
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Thus, after many promising preclinical outcomes, we have numerous failed clinical trials in stroke. Many of these can be explained on the basis of inadequate preclinical data, poor clinical trial design, or a mismatch between the preclinical findings and the clinical studies; some failures remain inexplicable. This has caused a serious reanalysis of our experimental approaches to stroke, including the rigor of the experimental work and the relevance of commonly used methods (1–5). To date, the vast majority of experimental studies on stroke have used young male rodents, with no confounding comorbidities, no parallel treatments, and no consequences of stroke. Furthermore, few studies have used approaches which mimic the clinical causes of stroke to induce cerebral ischemia. Indeed most have employed mechanical occlusion of a major artery (the middle cerebral artery); very few have used thrombus or hemorrhage or indeed studied animals with spontaneous stroke. A further factor which may have influenced the apparent discrepancy between rodent studies and clinical trials may be that unsurprisingly, stroke has been considered as a neurological disorder given that the clinical outcomes are neurological. Yet stroke is profoundly influenced, and perhaps even caused, by systemic factors, including atherosclerosis, impaired cardiac function, systemic inflammation, and infection. It is clearly not feasible, or probably helpful, to fully mimic all the common clinical factors associated with stroke simultaneously in animals. To develop aged, atherosclerotic animals, some of which have diabetes, many hypertension and obesity, some would be smokers, have a poor diet and others would have many other confounding factors and comorbidities, as well as exposure to a whole ar
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