Absence of cellular stress in brain after hypoxia induced by arousal from hibernation in Arctic ground squirrels

Abstract

Although hypoxia tolerance in heterothermic mammals is well established, it is unclear whether the adaptive significance stems from hypoxia or other cellular challenge associated with euthermy, hibernation, or arousal. In the present study, blood gases, hemoglobin O 2 saturation (SO2), and indexes of cellular and physiological stress were measured during hibernation and euthermy and after arousal thermogenesis. Results show that arterial O 2 tension (PaO 2 ) and SO2 are severely diminished during arousal and that hypoxia-inducible factor (HIF)-1␣ accumulates in brain. Despite evidence of hypoxia, neither cellular nor oxidative stress, as indicated by inducible nitric oxide synthase (iNOS) levels and oxidative modification of biomolecules, was observed during late arousal from hibernation. Compared with rats, hibernating Arctic ground squirrels (Spermophilus parryii) are well oxygenated with no evidence of cellular stress, inflammatory response, neuronal pathology, or oxidative modification following the period of high metabolic demand necessary for arousal. In contrast, euthermic Arctic ground squirrels experience mild, chronic hypoxia with low SO 2 and accumulation of HIF-1␣ and iNOS and demonstrate the greatest degree of cellular stress in brain. These results suggest that Arctic ground squirrels experience and tolerate endogenous hypoxia during euthermy and arousal.torpor; ischemia; stroke; Spermophilus parryii; reperfusion; inflammation; oxidative stress HIBERNATION IS A UNIQUE PHYSIOLOGICAL STATE of prolonged periods of low body temperature, metabolism, blood flow, and other physiological processes that are disrupted by brief periodic arousal episodes when animals rewarm and reperfuse metabolically active tissues (7). During arousal thermogenesis, blood flow returns to brain and other organs in a reperfusionlike manner at a time of maximal oxygen demand (42, 58). Preservation of neuronal and other cellular morphology during low cerebral blood flow demonstrates that hibernating mammals tolerate pronounced fluctuations in blood flow (16,61). Physiological and cellular stress experienced during euthermy, hibernation, and arousal is less well characterized.Arterial oxygen tension (Pa O 2 ) and tissue lactate measurements show that hibernating ground squirrels are well oxygenated (16,20), sometimes exceeding values in the euthermic state (15). In contrast, oxygen supply may become limiting during arousal thermogenesis. Increases in brain tissue lactate levels during peak oxygen consumption during arousal from hibernation in bats suggest these animals experience oxygen deficiency during arousal and reperfusion (30). However, because tissue lactate was not reported for euthermic bats, it is unclear how brain tissue hypoxia experienced during arousal compares to the euthermic state. Moreover, Pa O 2 was not measured to address the relationship between blood and tissue oxygenation during euthermy, hibernation, and arousal. To characterize physiological challenges associated with arousal thermogenesis, we evaluated b...

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

“…This constitutes a significant metabolic stress, and it has been suggested that hibernators either constitutively express higher levels of antioxidant enzymes than non-hibernating species or that hibernators upregulate antioxidant enzymes to protect against oxidative damage. Indeed, hibernators have been reported to avoid oxidative stress associated with arousal (Ma et al 2005) and, similar to dwarf mice, show evidence of cellular stress resistance (Lindell et al 2005;Kurtz et al 2006;Dave et al 2006). We previously showed that 13-lined ground squirrels do not upregulate intracellular antioxidant enzyme activities in brain, heart or liver tissue during hibernation (Page et al 2009a).…”

Distribution of NMDA receptor subunit NR1 in Arctic ground squirrel central nervous system

“…Heterothermic mammals, i.e., mammals that hibernate, provide extreme examples of neuroprotection in both the hibernating and euthermic (non-hibernating) state (Frerichs and Hallenbeck, 1998;Zhou et al, 2001;Ma et al, 2005;Ross et al, 2006;Dave et al, 2006). These animals also show pronounced synaptic plasticity and evidence of adult cognitive enhancement following arousal from hibernation (Mihailovic et al, 1968;Weltzin et al, 2006).…”

Upregulation of intracellular antioxidant enzymes in brain and heart during estivation in the African lungfish Protopterus dolloi

“…In addition, the levels of these enzymes in tissues of S. tridecemlineatus are comparable to those in mammalian species that do not hibernate (Page et al unpublished), indicating that antioxidant enzyme levels are not constitutively high in hibernating species. In hibernating Arctic ground squirrels (S. parryii) cellular stress was absent during arousal (Ma et al 2005). On the other hand, oxidative damage occurs in intestinal tissue during hibernation of S. tridecemlineatus (Carey et al 2000).…”