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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15NS070779-01
Application #
7941089
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (52))
Program Officer
Bosetti, Francesca
Project Start
2010-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$435,300
Indirect Cost
Name
University of Alaska Fairbanks
Department
Type
Organized Research Units
DUNS #
615245164
City
Fairbanks
State
AK
Country
United States
Zip Code
99775
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
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
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) 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
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
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

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