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.
|Laughlin, Bernard W; Bailey, Isaac R; Rice, Sarah A et al. (2018) Precise Control of Target Temperature Using N6-Cyclohexyladenosine and Real-Time Control of Surface Temperature. Ther Hypothermia Temp Manag 8:108-116|
|Drew, Kelly L; Frare, Carla; Rice, Sarah A (2017) Neural Signaling Metabolites May Modulate Energy Use in Hibernation. Neurochem Res 42:141-150|
|Bhowmick, Saurav; Moore, Jeanette T; Kirschner, Daniel L et al. (2017) Acidotoxicity via ASIC1a Mediates Cell Death during Oxygen Glucose Deprivation and Abolishes Excitotoxicity. ACS Chem Neurosci 8:1204-1212|
|Bhowmick, Saurav; Moore, Jeanette T; Kirschner, Daniel L et al. (2017) Arctic ground squirrel hippocampus tolerates oxygen glucose deprivation independent of hibernation season even when not hibernating and after ATP depletion, acidosis, and glutamate efflux. J Neurochem 142:160-170|
|Bhowmick, Saurav; Drew, Kelly L (2017) Arctic ground squirrel resist peroxynitrite-mediated cell death in response to oxygen glucose deprivation. Free Radic Biol Med 113:203-211|
|Bailey, Isaac R; Laughlin, Bernard; Moore, Lucille A et al. (2017) Optimization of Thermolytic Response to A1 Adenosine Receptor Agonists in Rats. J Pharmacol Exp Ther 362:424-430|
|Drew, Kelly L; Wells, Matthew; McGee, Rebecca et al. (2016) Arctic ground squirrel neuronal progenitor cells resist oxygen and glucose deprivation-induced death. World J Biol Chem 7:168-77|
|Jinka, Tulasi R; Combs, Velva M; Drew, Kelly L (2015) Translating drug-induced hibernation to therapeutic hypothermia. ACS Chem Neurosci 6:899-904|
|Christian, Sherri L; Rasley, Brian T; Roe, Tanna et al. (2014) Habituation of Arctic ground squirrels (Urocitellus parryii) to handling and movement during torpor to prevent artificial arousal. Front Physiol 5:174|
|Bogren, Lori K; Murphy, Carl J; Johnston, Erin L et al. (2014) 1H-NMR metabolomic biomarkers of poor outcome after hemorrhagic shock are absent in hibernators. PLoS One 9:e107493|
Showing the most recent 10 out of 18 publications