Mechanisms of innate preconditioning towards ischemia/anoxia tolerance: Lessons from mammalian hibernators

Abstract

Hibernating mammals exhibit an innate physiological ability to withstand dramatic fluctuations in blood flow that occurs during hibernation and arousal or experimental models of ischemia reperfusion without significant damage. These innate adaptations are of significance particularly to organs that are highly susceptible to energy deprivation, such as the brain and the heart. Among vertebrates, the arctic ground squirrel (AGS) is a species that tolerates ischemic/anoxic insult. During the process of entering hibernation, a state of prolonged torpor, the AGS undergoes a profound decrease in respiratory rate, heart rate, blood flow, cerebral perfusion, and body temperature (Tb). The reduced level of blood flow during torpor resembles an ischemic state, albeit without energy deficit. During the process of arousal or emergence from torpor, however, when Tb, respiratory rate, heart rate, and blood flow rapidly returns to pre-torpid levels, the rapid return of cerebral blood flow mimics aspects of reperfusion such as is seen after stroke or cardiac arrest. This sublethal ischemic/reperfusion insult experienced by AGS during the process of arousal may precondition AGS to tolerate otherwise lethal ischemic/reperfusion injury induced in the laboratory. In this review, we will summarize some of the mechanisms implemented by mammalian hibernators to combat ischemia/anoxia tolerance.

Figure 1.

AGS tolerate OGD injury despite ATP loss and glutamate efflux (A) Schematic representation of possible pathway in AGS tolerance to injury. (B) Lactic acid dehydrogenase (LDH) in perfusates collected every 15 min increases in rat hippocampal slices exposed to oxygen-glucose deprivation (OGD) (rat, OGD), but not in rat slices exposed to artificial cerebral spinal fluid (aCSF) (rat, aCSF), nor in slices harvested from summer euthermic AGS and exposed to aCSF (seAGS, aCSF). A small amount of LDH is released from slices collected from seAGS and exposed to OGD (seAGS, OGD). *p < 0.05 rat aCSF vs. rat OGD, +p < 0.05 rat OGD vs. seAGS OGD, #p < 0.05 seAGS aCSF vs. seAGS OGD. (C) Levels of whole tissue ATP were determined over time following bath application of treatment in slices from (a) rat (aCSF versus OGD) and (b) seAGS (aCSF versus OGD) subjected to either 30 min of aCSF or OGD followed by 3 h reperfusion. Gray bar indicates insult period. Data shown are means ± SEM, *p < 0.05 versus aCSF. (D) Time-dependent excitatory neurotransmitter (glutamate) efflux in rat and seAGS hippocampal slices induced by 30 min OGD insult. (n = 17 slices from six rats, n = 14 slices from five seAGS). Gray bar indicates insult period. *p < 0.05 for OGD versus aCSF group. Data shown are means ± SEM. [Reprinted with permission from Bhowmick et al. 2017a.]

Figure 2.

(A) Graphical representation of peroxynitrite mediated oxygen-glucose deprivagtion (OGD) injury in ischemic susceptible rat and ischemic tolerant AGS (B) 3-Nitrotyrosine (3-NT) was measured in rat and AGS slices either subjected to NO donor along with OGD or subjected to O2•-donor along with OGD. *p< 0.05 vs. OGD, ⁺p< 0.05 vs. aCSF. Data shown are means ± SEM. [Reprinted with permission from Bhowmick et al. 2017.]