Arctic Ground Squirrel (Spermophilus Parryii) Hippocampal Neurons Tolerate Prolonged Oxygen—Glucose Deprivation and Maintain Baseline ERK1/2 and JNK Activation Despite Drastic ATP Loss

Abstract

Oxygen-glucose deprivation (OGD) initiates a cascade of intracellular responses that culminates in cell death in sensitive species. Neurons from Arctic ground squirrels (AGS), a hibernating species, tolerate OGD in vitro and global ischemia in vivo independent of temperature or torpor. Regulation of energy stores and activation of mitogen-activated protein kinase (MAPK) signaling pathways can regulate neuronal survival. We used acute hippocampal slices to investigate the role of ATP stores and extracellular signal-regulated kinase (ERK)1/2 and Jun NH 2 -terminal kinase (JNK) MAPKs in promoting survival. Acute hippocampal slices from AGS tolerated 30 mins of OGD and showed a small but significant increase in cell death with 2 h OGD at 371C. This tolerance is independent of hibernation state or season. Neurons from AGS survive OGD despite rapid ATP depletion by 3 mins in interbout euthermic AGS and 10 mins in hibernating AGS. Oxygen-glucose deprivation does not induce JNK activation in AGS and baseline ERK1/2 and JNK activation is maintained even after drastic depletion of ATP. Surprisingly, inhibition of ERK1/2 or JNK during OGD had no effect on survival, whereas inhibition of JNK increased cell death during normoxia. Thus, protective mechanisms promoting tolerance to OGD by AGS are downstream from ATP loss and are independent of hibernation state or season.

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

“…Dave et al 2006;Christian et al 2008), and estivation (Smith 1930;Smith 1931). Several authors (e.g.…”

“…The diapausing Caenorhabditis elegans (dauer larva; reviewed in Honda and Honda 2002) is resistant to a wide range of environmental stresses. Recent studies have shown also that brain and liver tissues of hibernating squirrels are characterized by increased oxidative stress resistance (Lindell et al 2005;Dave et al 2006;Christian et al 2008). An adaptive response to oxidative stress often includes increased synthesis and/or activity of intracellular antioxidant enzymes, which can protect cellular macromolecules from potentially lethal stress-induced damage.…”

Cellular Basis for Learning Impairment in Fragile X Syndrome

“…Liver and intestine isolated from the thirteen-lined ground squirrel during inter-bout arousal resist I/R injury; however, tolerance is lost or decreased when tissue is obtained from animals during the summer season (Kurtz et al, 2006; Lindell et al, 2005). By contrast, in AGS, tolerance to cerebral I/R in acute hippocampal slices is actually greater during the summer season than during winter inter-bout euthermy; where, only during inter-bout euthermy is any difference noted between active and hibernating ground squirrels (Christian et al, 2008). In other species, the state of hibernation seems to enhance tolerance relative to active (euthermic) animals and rats, although, as bath temperature is decreased, tolerance of brain slices from active animals approaches the degree of tolerance observed in slices from hibernating animals (Frerichs and Hallenbeck, 1998).…”

“…However, P aO 2 falls significantly during arousal from hibernation (Ma et al, 2005). Whether resistance to ischemic or hypoxic injury depends on the hibernation season, and thus seasonal expression of a hibernation phenotype, remains a matter of debate and may depend on the tissue and species studied (Christian et al, 2008;Kurtz et al, 2006). Here we provide a brief overview of hibernation and review evidence for resistance to ischemia/reperfusion (I/R) injury in hibernating species with emphasis on the arctic ground squirrel (AGS), Urocitellus parryii.…”

“…Firstly, glucose derived from glycogen is not expected to reach ischemic tissue when blood flow is stopped during cardiac arrest. Secondly, addition of iodoacetate, an inhibitor of glycolysis, which would negate any benefit from glycogen, as well as the addition of NaCN, an inhibitor of cellular respiration, which would prevent use of residual oxygen in the bath, during OGD fails to increase cell death in an acute slice preparation (Christian et al, 2008). In summary, arctic ground squirrels, similar to other hibernating rodents, experience periods of prolonged torpor when oxidative metabolism and other life-supporting processes are suspended for weeks at a time.…”