Out-of-hospital cardiac arrest (CA) affects more than 300,000 people annually in the United States, with morbidity and mortality rates that have not improved in 50 years. Therapeutic hypothermia is currently the only treatment shown to improve prognosis in CA patients. Torpor as seen in hibernating animals has potential to decrease brain injury during global cerebral ischemia by suppressing metabolic demand. This project arises from a recent breakthrough finding that activation of sensitized A1 adenosine receptors (A1AR) is sufficient to induce torpor in the arctic ground squirrel (AGS;Spermophilus parryii). Preliminary data show that a similar phenomenon of metabolic suppression can be mimicked in rats fed a restricted diet. The proposed studies will examine the potential role of central adenosine receptors in mediating the metabolism suppressing effect of dietary restriction (DR). We will then ask if DR suppression of metabolism occurs independently of its reduction of body temperature. Finally, we will ask if DR protects the brain against injury following global ischemia.

Public Health Relevance

The only therapy currently available for Out-of-Hospital Cardiac Arrest (CA) is hypothermia, which is thought to work in part by suppressing metabolism and hence the brain's need for oxygen. However, therapeutic hypothermia is complicated by untoward side-effects associated with cooling. The present research explores mechanisms used naturally in hibernating animals to suppress metabolism and the potential clinical utility of these mechanisms as prophylactic treatment for CA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-A (52))
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Bosetti, Francesca
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University of Alaska Fairbanks
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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
Combs, Vélvá M; Crispell, Heather D; Drew, Kelly L (2014) D-cycloserine 24 and 48 hours after asphyxial cardiac arrest has no effect on hippocampal CA1 neuropathology. J Cereb Blood Flow Metab 34:
Larson, John; Drew, Kelly L; Folkow, Lars P et al. (2014) No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J Exp Biol 217:1024-39
Bogren, Lori K; Olson, Jasmine M; Carpluk, Joanna et al. (2014) Resistance to systemic inflammation and multi organ damage after global ischemia/reperfusion in the arctic ground squirrel. PLoS One 9:e94225
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
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
Olson, Jasmine M; Jinka, Tulasi R; Larson, Lindy K et al. (2013) Circannual rhythm in body temperature, torpor, and sensitivity to A₁ adenosine receptor agonist in arctic ground squirrels. J Biol Rhythms 28:201-7
Jinka, Tulasi R; Duffy, Lawrence K (2013) Ethical considerations in hibernation research. Lab Anim (NY) 42:248-52
Jinka, Tulasi R; Rasley, Brian T; Drew, Kelly L (2012) Inhibition of NMDA-type glutamate receptors induces arousal from torpor in hibernating arctic ground squirrels (Urocitellus parryii). J Neurochem 122:934-40

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