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Hibernation: A Natural Model of Tolerance to Cerebral Ischemia/Reperfusion

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Innate Tolerance in the CNS

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Hibernation, a means of systemic energy conservation, defies the need for most life-sustaining processes. Hibernation is recognized by a state of prolonged torpor where whole body metabolic rate, core body temperature (T b), heart rate, and blood flow decrease to 1–10 % of values observed during sleep. These bouts of torpor are interrupted at regular intervals by brief episodes of heterogeneous rewarming and reperfusion of vital organs, including the brain. Despite the reduction of cerebral blood flow during torpor or the return of cerebral blood flow during interbout arousals, hibernation produces no evidence of neuropathology. Multiple adaptations, at the whole animal and tissue levels, during torpor reveal a combination therapy–like scenario that likely contributes to ischemic tolerance. Nonetheless, some hibernating species tolerate ischemic-like cerebral blood flow even when not hibernating outside of the hibernation season and when T b is maintained at 37 °C. The arctic ground squirrel (Urocitellus parryii), a species studied extensively as a model of cerebral ischemia tolerance, resists neuronal pathology following cardiac arrest in vivo and following various paradigms designed to mimic cerebral ischemia in brain slices and cultured neurons. Here we review evidence that supports and refutes hypothesized mechanisms of ischemia tolerance in arctic ground squirrels with the caveat that much remains to be learned about mechanisms of ischemia tolerance in arctic ground squirrels and in other mammalian hibernators. Although hibernating mammals resist injury following cerebral ischemia/reperfusion even when not hibernating, torpor nonetheless is a phenotype with obvious neuroprotective advantages including cold tissue temperatures, a decrease in metabolic demand, and suppressed immune responsiveness. Thus we also review recent breakthroughs in the understanding of how the central nervous system regulates the onset of hibernation and discuss prospects for inducing hibernation in humans.

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References

  • Anderson TR, Jarvis CR, Biedermann AJ, Molnar C, Andrew RD (2005) Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices. J Neurophysiol 93:963–979

    Article  PubMed  CAS  Google Scholar 

  • Barros RC, Branco LG (2000) Role of central adenosine in the respiratory and thermoregulatory responses to hypoxia. Neuroreport 11:193–197

    Article  PubMed  CAS  Google Scholar 

  • Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR (2000) Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 48:285–296

    Article  PubMed  CAS  Google Scholar 

  • Bickler PE, Fahlman CS (2004) Moderate increases in intracellular calcium activate neuroprotective signals in hippocampal neurons. Neuroscience 127:673–683

    Article  PubMed  CAS  Google Scholar 

  • Blackstone E, Roth MB (2007) Suspended animation-like state protects mice from lethal hypoxia. Shock 27:370–372

    Article  PubMed  CAS  Google Scholar 

  • Blackstone E, Morrison M, Roth MB (2005) H2S induces a suspended animation-like state in mice. Science 308:518

    Article  PubMed  CAS  Google Scholar 

  • Bouma HR, Kroese FG, Kok JW, Talaei F, Boerema AS, Herwig A, Draghiciu O, van Buiten A, Epema AH, van Dam A et al (2011) Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate. Proc Natl Acad Sci USA 108:2052–2057

    Article  PubMed  Google Scholar 

  • Bullard RW, David G, Nichols CT (eds) (1960) The mechanisms of hypoxic tolerance in hibernating and non-hibernating mammals. In: Mammalian hibernation. Museum of Comparative Zoology at Harvard College, Cambridge, MA

    Google Scholar 

  • Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729–738

    Article  PubMed  CAS  Google Scholar 

  • Carey HV, Andrews MT, Martin SL (2003) Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev 83:1153–1181

    PubMed  CAS  Google Scholar 

  • Chen Y, Cantrell AR, Messing RO, Scheuer T, Catterall WA (2005) Specific modulation of Na+  channels in hippocampal neurons by protein kinase C epsilon. J Neurosci 25:507–513

    Article  PubMed  CAS  Google Scholar 

  • Christian SL, Ross AP, Zhao HW, Kristenson HJ, Zhan X, Rasley BT, Bickler PE, Drew KL (2008) Arctic ground squirrel (Spermophilus parryii) hippocampal neurons tolerate prolonged oxygen-glucose deprivation and maintain baseline ERK1/2 and JNK activation despite drastic ATP loss. J Cereb Blood Flow Metab 28:1307–1319

    Article  PubMed  CAS  Google Scholar 

  • Contestabile A (2009) Benefits of caloric restriction on brain aging and related pathological states: understanding mechanisms to devise novel therapies. Curr Med Chem 16:350–361

    Article  PubMed  CAS  Google Scholar 

  • D’Alecy LG, Lundy EF, Kluger MJ, Harker CT, LeMay DR, Shlafer M (1990) Beta-hydroxybutyrate and response to hypoxia in the ground squirrel, Spermophilus tridecimlineatus. Comp Biochem Physiol B 96:189–193

    Article  PubMed  Google Scholar 

  • Dausmann KH, Glos J, Ganzhorn JU, Heldmaier G (2004) Physiology: hibernation in a tropical primate. Nature 429:825–826

    Article  PubMed  CAS  Google Scholar 

  • Dave KR, Prado R, Raval AP, Drew KL, Perez-Pinzon MA (2006) The Arctic ground squirrel brain is resistant to injury from cardiac arrest during euthermia. Stroke 37(5):1261–1265

    Article  PubMed  CAS  Google Scholar 

  • Dave KR, Anthony Defazio R, Raval AP, Dashkin O, Saul I, Iceman KE, Perez-Pinzon MA, Drew KL (2009) Protein kinase C epsilon activation delays neuronal depolarization during cardiac arrest in the euthermic arctic ground squirrel. J Neurochem 110:1170–1179

    Article  PubMed  CAS  Google Scholar 

  • Derwall M, Westerkamp M, Lower C, Deike-Glindemann J, Schnorrenberger NK, Coburn M, Nolte KW, Gaisa N, Weis J, Siepmann K et al (2010) Hydrogen sulfide does not increase resuscitability in a porcine model of prolonged cardiac arrest. Shock 34:190–195

    Article  PubMed  CAS  Google Scholar 

  • Drew KL, Rice ME, Kuhn TB, Smith MA (2001) Neuroprotective adaptations in hibernation: therapeutic implications for ischemia-reperfusion, traumatic brain injury and neurodegenerative diseases. Free Radic Biol Med 31:563–573

    Article  PubMed  CAS  Google Scholar 

  • Drew KL, Christian SL, Jinka TR, Hollen L, Dehn J (2009) “Natural” tolerance in hibernators: can we learn from physiological and preconditioning against ischemic or hypoxic brain injury? In: Schaller BJ (ed) Ischemic tolerance of the brain. Research Signpost, Trivandrum, pp 1–44

    Google Scholar 

  • Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    Article  PubMed  CAS  Google Scholar 

  • Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C et al (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 104:15560–15565

    Article  PubMed  CAS  Google Scholar 

  • Frerichs KU, Hallenbeck JM (1998) Hibernation in ground squirrels (AGS) induces state and species-specific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices. J Cereb Blood Flow Metab 18:168–175

    Article  PubMed  CAS  Google Scholar 

  • Frerichs KU, Kennedy C, Sokoloff L, Hallenbeck JM (1994) Local cerebral blood flow during hibernation, a model of natural tolerance to “cerebral ischemia”. J Cereb Blood Flow Metab 14:193–205

    Article  PubMed  CAS  Google Scholar 

  • Geiser F, Ruf T (1995) Hibernation versus daily torpor in mammals and birds: physiological variables and classification of torpor patterns. Physiol Zool 68:935–966

    Google Scholar 

  • Hochachka PW (1986) Defense strategies against hypoxia and hypothermia. Science 231:234–241

    Article  PubMed  CAS  Google Scholar 

  • Hoffman RA, Robinson PF, Magalhaes H (eds) (1968) The Golden Hamster; its biology and use in medical research. The Iowa State University Press, Ames

    Google Scholar 

  • Jackson DC (2004) Acid-base balance during hypoxic hypometabolism: selected vertebrate strategies. Respir Physiol Neurobiol 141:273–283

    Article  PubMed  CAS  Google Scholar 

  • Jinka TR, Carlson ZA, Moore JT, Drew KL (2010) Altered thermoregulation via sensitization of A1 adenosine receptors in dietary restricted rats. Psychopharmacology (Berl) 209(3):217–224

    Article  CAS  Google Scholar 

  • Jinka TJ, Toien O, Drew KL (2011) Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A1 receptors. J Neurosci 31(30):10752–10758

    Article  PubMed  CAS  Google Scholar 

  • Kirschner DL, Wilson AL, Drew KL, Green TK (2009) Simultaneous efflux of endogenous D-ser and L-glu from single acute hippocampus slices during oxygen glucose deprivation. J Neurosci Res 87:2812–2820

    Article  PubMed  CAS  Google Scholar 

  • Kurtz CC, Lindell SL, Mangino MJ, Carey HV (2006) Hibernation confers resistance to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 291:G895–G901

    Article  PubMed  CAS  Google Scholar 

  • Lechler E, Penick GD (1963) Blood clotting defect in hibernating ground squirrels (AGS) (Citellus tridecemlineatus). Am J Physiol 205:985–988

    PubMed  CAS  Google Scholar 

  • Lee M, Choi I, Park K (2002) Activation of stress signaling molecules in bat brain during arousal from hibernation. J Neurochem 82:867–873

    Article  PubMed  CAS  Google Scholar 

  • Lee YJ, Miyake S, Wakita H, McMullen DC, Azuma Y, Auh S, Hallenbeck JM (2007) Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells. J Cereb Blood Flow Metab 27:950–962

    PubMed  CAS  Google Scholar 

  • Lindell SL, Klahn SL, Piazza TM, Mangino MJ, Torrealba JR, Southard JH, Carey HV (2005) Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol 288:G473–G480

    Article  PubMed  CAS  Google Scholar 

  • Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    PubMed  CAS  Google Scholar 

  • Lutz PL, Milton SL (2004) Negotiating brain anoxia survival in the turtle. J Exp Biol 207:3141–3147

    Article  PubMed  CAS  Google Scholar 

  • Ma YL, Zhu X, Rivera PM, Toien O, Barnes BM, LaManna JC, Smith MA, Drew KL (2005) Absence of cellular stress in brain after hypoxia induced by arousal from hibernation in Arctic ground squirrels (AGS). Am J Physiol Regul Integr Comp Physiol 289:R1297–R1306

    Article  PubMed  CAS  Google Scholar 

  • Nowak G, Bakajsova D, Clifton GL (2004) Protein kinase C-epsilon modulates mitochondrial function and active Na+  transport after oxidant injury in renal cells. Am J Physiol Renal Physiol 286:F307–F316

    Article  PubMed  CAS  Google Scholar 

  • Orr AL, Lohse LA, Drew KL, Hermes-Lima M (2009) Physiological oxidative stress after arousal from hibernation in Arctic ground squirrel. Comp Biochem Physiol A Mol Integr Physiol 153:213–221

    Article  PubMed  Google Scholar 

  • Osborne PG, Hashimoto M (2005) Brain antioxidant levels in hamsters during hibernation, arousal and cenothermia. Behav Brain Res 175(3):147–55

    Google Scholar 

  • Osborne PG, Sato J, Shuke N, Hashimoto M (2005) Sympathetic alpha-adrenergic regulation of blood flow and volume in hamsters arousing from hibernation. Am J Physiol Regul Integr Comp Physiol 289:R554–R562

    Article  PubMed  CAS  Google Scholar 

  • Pivorun EB, Sinnamon WB (1981) Blood coagulation studies in normothermic, hibernating, and aroused Spermophilus franklini. Cryobiology 18:515–520

    Article  PubMed  CAS  Google Scholar 

  • Prendergast BJ, Freeman DA, Zucker I, Nelson RJ (2002) Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels (AGS). Am J Physiol Regul Integr Comp Physiol 282:R1054–R1062

    PubMed  CAS  Google Scholar 

  • Ross AP, Christian SL, Zhao HW, Drew KL (2006) Persistent tolerance to oxygen and nutrient deprivation and N-methyl-D-aspartate in cultured hippocampal slices from hibernating Arctic ground squirrel. J Cereb Blood Flow Metab 26:1148–1156

    PubMed  CAS  Google Scholar 

  • Savitz SI, Fisher M (2007a) Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol 61:396–402

    Article  PubMed  CAS  Google Scholar 

  • Savitz SI, Fisher M (2007b) Prophylactic neuroprotection. Curr Drug Targets 8:846–849

    Article  PubMed  CAS  Google Scholar 

  • Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86:1659–1669

    Article  PubMed  CAS  Google Scholar 

  • Shiomi H, Tamura Y (2000) Pharmacological aspects of mammalian hibernation: central thermoregulation factors in hibernation cycle. Nippon Yakurigaku Zasshi (Folia Pharmacol Jpn) 116:304–312

    Article  CAS  Google Scholar 

  • Snider BJ, Tee LY, Canzoniero LM, Babcock DJ, Choi DW (2002) NMDA antagonists exacerbate neuronal death caused by proteasome inhibition in cultured cortical and striatal neurons. Eur J Neurosci 15:419–428

    Article  PubMed  Google Scholar 

  • Steiner AA, Branco LG (2002) Hypoxia-induced anapyrexia: implications and putative mediators. Annu Rev Physiol 64:263–288

    Article  PubMed  CAS  Google Scholar 

  • Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, Mori M, Meller R, Rosenzweig HL, Tobar E, Shaw TE et al (2003) Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362:1028–1037

    Article  PubMed  CAS  Google Scholar 

  • Stowe AM, Altay T, Freie AB, Gidday JM (2011) Repetitive hypoxia extends endogenous neurovascular protection for stroke. Ann Neurol 69:975–985

    Article  PubMed  CAS  Google Scholar 

  • Swoap S, Lliff B (2011) AMP vs. Adenosine as a mediator of fasting-induced torpor. Paper presented at: metabolic responses to extreme conditions (Big Sky, Montana, Keystone Symposia on Molecular and Cellular Biology)

    Google Scholar 

  • Swoap SJ, Rathvon M, Gutilla M (2007) AMP does not induce torpor. Am J Physiol Regul Integr Comp Physiol 293:R468–R473

    Article  PubMed  CAS  Google Scholar 

  • Tahti H, Soivio A (1975) Blood gas concentrations, acid-base balance and blood pressure in hedgehogs in the active state and in hibernation with periodic respiration. Ann Zool Fennici 12:188–192

    CAS  Google Scholar 

  • Takeda Y, Namba K, Higuchi T, Hagioka S, Takata K, Hirakawa M, Morita K (2003) Quantitative evaluation of the neuroprotective effects of hypothermia ranging from 34 degrees C to 31 degrees C on brain ischemia in gerbils and determination of the mechanism of neuroprotection. Crit Care Med 31:255–260

    Article  PubMed  Google Scholar 

  • Tattersall GJ, Milsom WK (2003) Transient peripheral warming accompanies the hypoxic metabolic response in the golden-mantled ground squirrel. J Exp Biol 206:33–42

    Article  PubMed  Google Scholar 

  • Toien O, Drew KL, Chao ML, Rice ME (2001) Ascorbate dynamics and oxygen consumption during arousal from hibernation in Arctic ground squirrels (AGS). Am J Physiol Regul Integr Comp Physiol 281:R572–R583

    PubMed  CAS  Google Scholar 

  • Toien O, Blake J, Edgar DM, Grahn DA, Heller HC, Barnes BM (2011) Hibernation in black bears: independence of metabolic suppression from body temperature. Science 331:906–909

    Article  PubMed  CAS  Google Scholar 

  • Toombs CF, Insko MA, Wintner EA, Deckwerth TL, Usansky H, Jamil K, Goldstein B, Cooreman M, Szabo C (2010) Detection of exhaled hydrogen sulphide gas in healthy human volunteers during intravenous administration of sodium sulphide. Br J Clin Pharmacol 69:626–636

    Article  PubMed  CAS  Google Scholar 

  • Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R (2008) Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res 102:519–528

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Kaasik K, Blackburn MR, Lee CC (2006) Constant darkness is a circadian metabolic signal in mammals. Nature 439:340–343

    Article  PubMed  CAS  Google Scholar 

  • Zhao HW, Ross AP, Christian SL, Buchholz JN, Drew KL (2006) Decreased NR1 phosphorylation and decreased NMDAR function in hibernating Arctic ground squirrels (AGS). J Neurosci Res 84:291–298

    Article  PubMed  CAS  Google Scholar 

  • Zhou F, Zhu X, Castellani RJ, Stimmelmayr R, Perry G, Smith MA, Drew KL (2001) Hibernation, a model of neuroprotection. Am J Pathol 158:2145–2151

    Article  PubMed  CAS  Google Scholar 

  • Zhu PJ, Krnjevic K (1997) Adenosine release mediates cyanide-induced suppression of CA1 neuronal activity. J Neurosci 17:2355–2364

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the US Army Research Office W911NF-05-1-0280, the US Army Medical Research and Materiel Command 05178001, the National Institute of Neurological Disorders and Stroke NS041069-06 and R15NS070779, and Alaska INBRE and Alaska EPSCoR. The authors acknowledge Bianca Zuckerman for assistance with MRI angiography and data analysis. The authors also acknowledge Daniel Kirschner, Thomas Green and Kili Wetherell for assistance with microperfusion experiments and glutamate analysis.

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Authors and Affiliations

  1. Institute of Arctic Biology, Alaska Basic Neuroscience Program, University of Alaska Fairbanks, 902 N. Koyukuk Dr., Fairbanks, AK, 99775-7000, USA

    Kelly L. Drew Ph.D., Lori K. Bogren, Tulasi R. Jinka & Jeanette T. Moore

  2. Radiology Consultants, Inc., Fairbanks, AK, USA

    Jeffrey A. Zuckerman & Phillip E. Shenk

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  1. Kelly L. Drew Ph.D.
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  2. Jeffrey A. Zuckerman
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  3. Phillip E. Shenk
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  4. Lori K. Bogren
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  5. Tulasi R. Jinka
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  6. Jeanette T. Moore
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Correspondence to Kelly L. Drew Ph.D. .

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Editors and Affiliations

  1. , Departments of Neurosurgery, Washington University School of Medicine, South Kingshighway Boulevard, St. Louis, 63110, Missouri, USA

    Jeffrey M. Gidday

  2. , Department of Neurology, University of Miami Miller School of Med, Miami, 33136, Florida, USA

    Miguel A. Perez-Pinzon

  3. Loma Linda University, 11234 Anderson Street, Room 2562B, Loma Linda, 92354, California, USA

    John H. Zhang

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Drew, K.L., Zuckerman, J.A., Shenk, P.E., Bogren, L.K., Jinka, T.R., Moore, J.T. (2013). Hibernation: A Natural Model of Tolerance to Cerebral Ischemia/Reperfusion. In: Gidday, J., Perez-Pinzon, M., Zhang, J. (eds) Innate Tolerance in the CNS. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9695-4_3

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