Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemia tolerance

Abstract

Torpor during hibernation defines the nadir of mammalian metabolism where whole animal rates of metabolism are decreased to as low as 2% of basal metabolic rate. This capacity to decrease profoundly the metabolic demand of organs and tissues has the potential to translate into novel therapies for the treatment of ischemia associated with stroke, cardiac arrest or trauma where delivery of oxygen and nutrients fails to meet demand. If metabolic demand could be arrested in a regulated way, cell and tissue injury could be attenuated. Metabolic suppression achieved during hibernation is regulated, in part, by the central nervous system through indirect and possibly direct means. In this study, we review recent evidence for mechanisms of central nervous system control of torpor in hibernating rodents including evidence of a permissive, hibernation protein complex, a role for A1 adenosine receptors, mu opiate receptors, glutamate and thyrotropin-releasing hormone. Central sites for regulation of torpor include the hippocampus, hypothalamus and nuclei of the autonomic nervous system. In addition, we discuss evidence that hibernation phenotypes can be translated to non-hibernating species by H 2 S and 3-iodothyronamine with the caveat that the hypothermia, bradycardia, and metabolic suppression induced by these compounds may or may not be identical to mechanisms employed in true hibernation. Keywords metabolic arrest; metabolic suppression; suspended animationHibernating animals display a variety of adaptations that protect the central nervous system from metabolic challenges and trauma that are injurious in non-hibernating species. These adaptations include profound decreases in brain and body temperature (T b ) and immune function, enhanced antioxidant defenses, and metabolic suppression Zhou et al. 2001; Ross et al. 2006). Metabolic suppression, a regulated and reversible reduction in cellular and tissue need for oxygen and nutrients, matches metabolic demand with supply and is one of the most novel yet least well-understood neuroprotective aspects of hibernation. Knowledge of mechanisms used by hibernating animals to decrease metabolic demand to as low as 2% of basal metabolic rate or 0.01 mL O 2 /g/h

Natural Protection Against Cardiac Arrhythmias During Hibernation: Significance of Adenosine

“…Central nervous system regulation of hibernation is implicated by several studies (Drew et al, 2007;Jinka et al, 2011). Recent study has shown that administration of the adenosine A1 receptor agonist N 6 -cyclohexyladenosine (CHA) into the lateral ventricle of arctic ground squirrel induces hibernation.…”

“…A growing body of evidence supports the significance of adenosine in hibernation (Drew et al, 2007). Adenosine is a widely distributed inhibitory neuromodulator throughout the central nervous system including the brainstem, the principle cardiovascular control center (Mosqueda-Garcia et al, 1989;Barraco and Phillis, 1991).…”

“…Successful translation of hibernation to non-hibernating species will open possibilities of applying the concept of metabolic suppression and low body temperature to humans in treating conditions such as stroke, hemorrhagic shock, cardiac arrest, cerebral ischemia, and multiorgan failure (Drew et al, 2007).…”

“…[source: (Drew et al, 2009)] 2.2 The steady-state phase Animal enters into a steady-state phase of hibernation after a few hours of initiation of torpor. Steady-state phase represents the nadir of mammalian heart rate, metabolism, and core body temperature (Drew et al, 2007) where the animal maintains its lowest heart rate, metabolism, and core body temperature for about 1-3 weeks (Boyer and Barnes, 1999;Buck and Barnes, 2000;Carey et al, 2003a). An occasional burst of activity paralleled with an increase in heart rate, metabolism and heat production is observed during this phase and is hypothesized as a measure to avoid decreases in body temperature beyond a certain point (Heldmaier et al, 2004).…”

“…Core body temperature and heart rate were measured with an ip transmitter as described previously (Jinka et al, 2011). Torpor in hibernation is broadly divided into three phasesentrance, steady-state, and arousal (Boyer and Barnes, 1999;Carey et al, 2003a;Heldmaier et al, 2004;Drew et al, 2007). Entrance phase is followed by steady-state phase which lasts for 1-3 weeks before the arousal phase is initiated.…”