ReviewNeuroprotection: Lessons from hibernators
Introduction
Hibernation is identified by a prolonged state of energy conservation, termed torpor, that allows heterothermic mammals to tolerate the limited resource availability encountered in extreme environments (Drew et al., 2007). During the hibernation season, hibernating animals experience multiple bouts of torpor that are interrupted by brief periods of euthermia. Torpor can be divided into three phases, onset, maintenance and arousal, which are followed by a period of interbout euthermia. During onset and maintenance of torpor, animals exhibit overall metabolic suppression, decreased body temperature, reduction in heart rate, reduction in cerebral blood flow, decreased oxygen consumption, lowered respiratory rates and suppressed immune responses (Barnes, 1989, Buck and Barnes, 2000, Toien et al., 2001, Drew et al., 2002, Barger et al., 2003, Drew et al., 2004, Drew et al., 2009). During arousal from torpor, rapid blood reperfusion is accompanied by enormous oxygen consumption and elevation in body temperature. Inflammatory and immune responses resume, and the capacity to scavenge free radicals is increased (Barnes, 1989, Toien et al., 2001, Prendergast et al., 2002, Bouma et al., 2011). Interbout euthermia is characterized by metabolism, blood flow and body temperature typical of a homeothermic mammal of similar size (Drew et al., 2004).
In the hibernating phase, an animal's oxygen demand is decreased to as low as 2% of euthermic oxygen demand and cerebral blood flow is decreased to as low as 10% of the euthermic phase (Drew et al., 2002, Drew et al., 2009). Even when not hibernating, arctic ground squirrels (AGS) (Urocitellus parryii) can tolerate at least 10 min of global ischemia without detectable neuronal injury (Dave et al., 2006, Dave et al., 2009). Understanding the mechanism by which hibernators tolerate such a drastic reduction in cerebral blood flow and achieve this profound metabolic suppression has the potential to facilitate the design of novel therapies for diseases or conditions where interruptions in blood flow to the brain are inherent. In this review, we discuss the major mechanisms by which cerebral ischemic injury may be avoided during hibernation. We also present the current understanding of how the brain of hibernating species are protected from cerebral ischemia when euthermic.
We also present data that support our hypothesis (Fig. 1) that hibernators have evolved physiological adaptations as a result of selective pressures associated with transitions into and out of torpor. These adaptations may have materialized as tolerance to cerebral ischemia during euthermia and an increased capacity for adult synaptic plasticity.
Section snippets
Torpor
Decreased body temperature and metabolic suppression are the two main characteristics of torpor (Drew et al., 2007, Drew et al., 2009). In very small hibernators, metabolic suppression may be regulated by temperature-dependent passive processes. In contrast, in relatively large hibernators metabolic suppression clearly precedes the temperature drop, as detected by greatly diminished oxygen consumption, suggesting a large contribution of temperature-independent processes (Geiser, 2004, Drew et
Euthermic phase
In vitro studies demonstrate resistance to modeled ischemia in hippocampus from both hAGS and ibeAGS compared to the more ischemia-sensitive rat (Ross et al., 2006). Brains of ibeAGS retain a significant capacity to tolerate energy deprivation even when not in a torpid state. Tolerance in ibeAGS appears to involve channel arrest, but of a more limited scope than the channel arrest that occurs during torpor in hAGS. Relative to rat, glutamate-induced Ca2 + influx is suppressed in both hAGS and
Summary
Mammals capable of hibernation represent a robust example of tolerance to cerebral ischemia that is unmatched by any other model of ischemia tolerance. Hibernation is characterized by profound decreases in metabolic demand and body temperature as well as decreased blood flow does not produce an ischemic state. Brief, interbout arousals occur frequently throughout the hibernation season and appear to be the most physiologically challenging aspect of heterothermy where blood flow may not meet
Acknowledgement
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, R15NS070779, NS45676-01, NS054147-01, and NS34773. We thank Dr. Brant D. Watson for critical reading of the manuscript.
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