Early reperfusion is of proven benefit in stroke but intervention is only effective after brief ischemia, and it is critical that methods be found to extend its therapeutic window. Delayed, brief hypothermia can reduce infarct volume after focal ischemia in several rat models, provided cooling is initiated prior to or soon after the onset of recirculation. Preliminary results indicate significant strain differences in this effect, with a more prolonged window for intervention in Long-Evans rats, suggesting that cooling is particularly protective against """"""""reperfusion injury"""""""" that is an established feature of this model. A novel approach is the selective cooling of blood reperfusing the previously ischemic territory, specifically targeting tissue at risk and reducing the potential for complications associated with deep systemic hypothermia. This robust model provides an opportunity to both define the practical limits of hypothermic protection and identify mechanisms by which hypothermia impacts postischemic injury cascades. Proposed studies will: 1) fully define the range of insult duration and temperature modulation over which protection can be achieved; 2) determine the impact of protective cooling on molecular markers of postischemic injury in neurons and other cell types; and 3) elucidate the impact of cooling on intravascular injury mechanisms that may contribute to infarct evolution. These results will establish the relative accessibility of intravascular vs. parenchymal injury cascades to hypothermic protection, and define critical targets for pharmacological intervention.
