Grant: Project Grant

Stroke affects over 62,000 Canadians each year. Most cases result from a blood clot that impairs blood flow to part of the brain. Brain damage occurs when this ischemia is severe or prolonged, and that leads to behavioral and cognitive deficits or even death. There are clinically approved pharmacological and mechanical therapies to remove clots, which when done quickly can rescue brain tissue and improve outcome. Sadly, some do not benefit from clot removal. Those patients are left with life-long disability. We will use rats to model those patients with severe stroke who receive modest to no benefit from clot removal, as these patients desperately need additional treatments. We will test a combination of hypothermia therapies that should reduce brain injury and improve behavioral outcome. The first involves infusing intra-arterial cold saline (20°C) into the ischemic brain for 20 min at the time blood flow is restored (clot removal time in patients). This should improve blood flow and attenuate injury. Second, we will test whether adding external head cooling (e.g., brain temperature at 35°C for up to a day) will further lessen brain damage. These therapies have many beneficial effects, such as reducing brain swelling, and we expect that they will improve outcome after this severe stroke. However, while these cooling therapies work in certain animal models and settings, existing studies were quite limited in scope, and there was little done to evaluate combination treatments against severe stroke. Thus, we will test these therapies using translationally rigorous, clinically relevant endpoints and experimental design features (e.g., high statistical power, use of hypertensive animals, and comparisons of aged male and female animals). Our goals are to identify the best hypothermia therapy to inform upcoming clinical trials on therapeutic cooling, and to further improve our mechanistic knowledge of these treatments.