In recent years there has been a resurgence of interest in mild hypothermia (30-35 degrees C) as a method of cerebral protection. This project aims at defining optimal parameters in which mild hypothermia can be applied in animal models of focal stroke and explores the mechanisms of neuroprotection by which temperature manipulations and pharmacological intervention may work. Using an intraluminal suture occlusion model of focal cerebral ischemia in the rat, a series of experiments will be performed to: 1) determine the optimal depth and duration of hypothermia which provides maximal reduction in infarct size while avoiding systemic complications; 2) address the extent to which hypothermia can be delayed and still be neuroprotective as well as whether the protective effects are sustained over time; 3) determine if mild hypothermia protects against both permanent and transient focal ischemia; 4) characterize the physiological changes resulting from mild hypothermia under ischemic conditions including its effects on metabolism, excitatory amino acid release, cerebral blood flow, and blood-brain-barrier integrity; and 5) determine whether the neuroprotective effects of mild hypothermia and glutamate receptor antagonists are additive. In order to examine the feasibility of hypothermia in a potential clinical setting, hypothermia will be used in conjunction with a thrombolytic agent in a rabbit model of thromboembolic stroke. The time course of ischemia and response to treatment with hypothermia and thrombolysis will be monitored using sequential diffusion and perfusion MRIs. This project will also investigate the use of diffusion-weighted MRI (DWI) in characterizing ischemic stroke in response to alterations in brain temperature. The time course of diffusion changes and infarct size will be studied as well as the potential of DWI as a predictor of infarct severity. The knowledge gained from this project will have direct implications for the treatment of ischemic stroke in humans including its use in both medical and surgical patients with cerebrovascular disease.
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