Brain ischemia results in permanent disability and death for thousands of patients annually. Hypothermia improves neurological outcome after brain ischemia, but has been slow to be accepted in clinical practice because of concerns about the efficacy and complexity of the therapy. Forced hypothermia is currently used clinically to lower body temperature and works by overwhelming the body's thermoregulatory mechanisms that resist cooling. However, physiological responses to forced cooling (shivering, vasoconstriction and release of stress hormones) reduce the efficacy of hypothermia. Drug-induced regulated hypothermia is proposed as a simple, effective new neuroprotective method that can be used clinically to rapidly lower body temperature after brain ischemia. Regulated hypothermia is a lowering of the brain's set- point temperature, resulting in a rapid and controlled reduction in body temperature. Hibernating mammals effectively use regulated hypothermia to protect the brain and heart from prolonged hypoxic-ischemia. It follows that the development of drugs to induce regulated hypothermia is the next step to improve neurological outcome from brain ischemia in humans. Ethanol and neurotensin both induce regulated hypothermia in animals and humans. Since the pharmacological and safety profile of ethanol in humans is well established, it is likely to proceed to clinical trials sooner than neurotensin and thus the reason for inclusion in this translational proposal. The following specific aims are proposed; Specific aim 1a: Compare regulated to forced hypothermia for time to target temperature, survival and neurological outcome after resuscitation from brain ischemia. Specific aim 1b: Determine the effect of rewarming rate on incidence of significant adverse events after regulated and forced hypothermia. The translational value of drug-induced regulated hypothermia will be examined in a rat outcome model that simulates the complex human pathophysiology of ischemic brain injury and neurological outcome. The main outcome measures of the study will be survival and neurological outcome. Neurological outcome will be evaluated by performance in the Morris Water Maze to assess spatial learning and memory. Secondary outcome measures include time to reach therapeutic hypothermia and incidence of complications with rewarming. Positive results from this study will provide compelling data to proceed with an application to the FDA for an investigational new drug application and clinical trial development. The long term goals of the project are to optimize hypothermia and rewarming to improve neurological outcome from a broad range of ischemic brain injuries.
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