Neurons are generally viewed as among the most sensitive of all cells when faced with hypoxia (periods of low oxygen) or anoxia (no oxygen), though recent studies have shown a wide variation in the capacity of neurons to tolerate hypoxia. Even the most vulnerable neurons are not defenseless, and the most tolerant can withstand extreme periods of complete anoxia and recover fully, despite oxidant damage when oxygen returns. There is currently an increasing interest in anoxia-tolerant vertebrates as models to identify survival strategies in neurons adapted to survive hypoxia and reperfusion. However, the mixed cellular responses observed in hypoxia-sensitive neurons have generated controversy over which molecular events are essential for cellular protection and which induce cell death. Serine/threonine kinase(Akt), for example, is a central molecule controlling the balance between cell survival and apoptosis, as well as cell proliferation and cell cycle arrest. Akt is considered to promote survival in many cell types, including neurons,where blocking Akt activation increases cell death in response to oxidative stress. Other researchers, however, report that the inhibition of Akt activity delays cell death, and the downregulation of Akt pathways in the nematode C. elegans causes it to shift into the energy conserving state known as the dauer larval stage.
John Hallenbeck and his associates at the National Institute of Neurological Disorders and Stroke were interested in whether Akt pathways in hibernating mammals are up- or downregulated, as hibernation is an evolutionary adaptation to harsh environmental conditions, like the dauer larval stage in C. elegans. Also, hibernating mammals often inhabit hypoxic burrows and, in hibernation, reduce blood flow to the brain, so are interesting models of neuronal hypoxic survival. In a recent issue of Brain Research, the researchers publish data describing Akt activity in hibernating 13-lined ground squirrels.
Wild-caught ground squirrels were placed in a cold chamber in constant darkness at 5°C. Akt levels and activity (phosphorylation) were compared in hibernating animals versus control (active, not cold-exposed) and cold-adapted (active, in cold chamber) ground squirrels. While there were no differences between groups in total Akt expression, Akt phosphorylation was significantly decreased in hibernating ground squirrels compared to active and cold-active groups. This reduction in phosphorylation was associated with a corresponding decrease in Akt kinase activity, and occurred in brain and other tissues including muscle, heart and kidney, indicating a generalized response. Akt kinase activity declined by nearly half in the brains of hibernating ground squirrels.
The authors admit that it appears paradoxical for Akt activity to decrease in hibernators, when increased activity is a known critical component of hypoxia survival through its downstream effects that increase survival. They hypothesize that similar survival pathways are at work in the hibernating ground squirrel and the dauer larval C. elegans; the downregulation of Akt pathways permits the upregulation of other pro-survival factors such as antioxidants, growth arrest, and DNA damage response genes.
As molecular pathways are often highly conserved across the phyla, the use of alternative model systems naturally tolerant to low oxygen and reperfusion stresses can reveal new targets for the potential treatment of stroke and other forms of organ ischemia.
