Mild therapeutic hypothermia improves outcome for patients resuscitated from cardiac arrest but has failed to show benefit for stroke patients. Poor efficacy in stroke is likely due in part to the difficulty of cooling conscious patients. Here we propose to induce therapeutic hypothermia in a rodent model of stroke via activation of brain A1 adenosine receptors (A1AR), a mechanism used by hibernating mammals to decrease body temperature during onset of hibernation. We will test the safety and efficacy of mild to moderate therapeutic hypothermia induced by the A1AR agonist 6N-cyclohexyladenosine (CHA) using telemetry and other techniques to monitor brain temperature, ECG, blood pressure and other physiological parameters during cooling and rewarming in conscious, freely moving rats. We will attempt to block adverse effects caused by stimulation of A1AR in the heart and other peripheral organs using 8-(p-sulfophenyl) theophylline (8-SPT), an adenosine receptor antagonist that does not penetrate the brain. We will also study the safety and efficacy of this approach to induce therapeutic hypothermia in a rat model of ischemic stroke. Preliminary data show that intermittent intraperitoneal injections of CHA and 8-SPT at an ambient temperature of 16oC maintain core body temperature between 30 and 32oC for 24h in rats without adverse consequences. This innovative approach to cooling mimics the mechanism used by hibernating animals to cool to near-ambient temperature and avoids the negative effects of shivering. In bypassing thermoregulatory defenses such as shivering, this research is highly significant because it is likely to refine techniques used to induce therapeutic hypothermia that may have significant benefit for stroke patients. At the same time, this application builds biomedical research infrastructure at the University of Alaska Fairbanks and brings biomedical research opportunities to Alaskan students, including a population of talented Alaska Native students who are underrepresented in biomedical research.
Therapeutic hypothermia is becoming the standard of care for comatose patients after cardiac arrest, but has proven difficult to implement in conscious stroke patients. This study applies principles of central nervous system regulation of body temperature in hibernating species to induce therapeutic hypothermia in conscious rats, and tests the efficacy of this approach to improve outcome following a rodent model of ischemic stroke.
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