Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes

Abstract

Human ischemic stroke is very complex and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients. As such, more and more disease models are being incorporated into the research design. This review highlights the major strengths and weaknesses of the most commonly used animal models of these conditions in preclinical stroke research. The goal is to provide guidance in choosing, reporting and executing appropriate disease models that will be subjected to different models of stroke injury.

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection

“…& Committee members recommended that aged animals be used for stroke research, comorbid conditions need to be represented (see [31,32,33]), chronic stroke models (months of survival) should be developed because rodents display adaptive plasticity, and stroke studies should incorporate atrial fibrillation, hypoperfusion, transient ischemic attack (TIA), and white matter damage. Most of these recommendations are consistent with previously stated STAIR recommendations [20].…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…DM raises the risk of cardiovascular and cerebrovascular diseases (such as ischemic stroke) multifolds 2. Approximately 30% of stroke patients have DM,2 and stroke in diabetic patients follows a specific clinical pattern mostly resulting in poor prognosis 3, 4. DM alters metabolism, and complicates stroke pathology, making it challenging to treat the diabetic ischemic brain.…”

To Improve Translational Research in Subarachnoid Hemorrhage

“…Genetic differences between animals and humans, and even within animal species, strains, and cell lines, may affect the immune responses and outcomes [10,12,13]. Third, stroke patients have many comorbidities or vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, cardiac diseases, current smoking, obesity, poor diet, inactivity, high alcohol intake, psychosocial stress and depression, social factors such as marital and residence status (i.e., living alone), and prestroke dysfunction, causing stroke severity [5,14]. Animal models having these factors are also subjected to different stroke injuries or changes in the structure of the neurovascular unit [14].…”

“…Third, stroke patients have many comorbidities or vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, cardiac diseases, current smoking, obesity, poor diet, inactivity, high alcohol intake, psychosocial stress and depression, social factors such as marital and residence status (i.e., living alone), and prestroke dysfunction, causing stroke severity [5,14]. Animal models having these factors are also subjected to different stroke injuries or changes in the structure of the neurovascular unit [14]. Thus, the use of young healthy animals causes a barrier for translation of findings to patients, while, in preclinical stroke studies with comorbidities, comorbidity duration and severity as well as housing conditions of the animals used, which potentially influence outcomes, should be reported in details.…”