The purpose of this research is to test the hypothesis that neuroprotection during hibernation and arousal is enhanced by a combination of factors including enhanced antioxidant defense and suppression of CNS metabolic demand.  A variety of techniques including microdialysis, organotypic brain slice culture and immunocytochemistry are used to assess neuronal cell response to brain injury and ischemia/aglycemia as well as rewarming from hibernation.  

Related Publications:
Zhou et al., 2001
Drew et al., 2001
Toein et al., 2001

And, see Science News

Background and Significance:

Stroke: Stroke, the consequence of an interruption of cerebral blood flow that can vary in severity from a passing weakness or tingling in a limb to a profound paralysis, coma and death, is the primary cause of disability in America.  Stroke-related mortality is twice as high in Alaskan Native populations as in non-native populations in both rural and urban areas  (Ebbesson et al., UAF, personal communication).  Clinical and experimental studies show that following an acute ischemic stroke, neuronal damage continues to progress for periods of several hours to days (Petito et al., 1987; Heiss et al., 1992; Garcia, 1992).  This time period is seen as a window of opportunity to allay progressive tissue damage.  Despite numerous therapeutic strategies found to reduce ischemia-induced damage in experimental models, only tissue plasminogen activator (TPA) has proven effective in controlled clinical trials (Adams et al., 1996; Wardlaw et al., 1997; Wahlgren, 1997).  While TPA has improved prognosis for many patients, progress in the development of effective pharmacotherapies has been slow. 

Neurodegenerative Disease: The pathological events in Alzheimer disease and late onset dementia may be triggered by or, at minimum, exacerbated by, impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in a breakdown of metabolic energy pathways in brain cells (Perry et al., 1998; de la Torre, 1999). Oxidative stress, the imbalance between processes leading to free radical production and the cellular antioxidant cascade, is likewise, intimately associated with the neurodegenerative process (reviewed in Smith et al., 2000). Hypoperfusion with subsequent disruption of energy balance and ion homeostasis and initiation of a cascade of events that ultimately leads to oxidative stress and cell death may thus be a common factor in neurodegeneration following stroke and in neurodegenerative disease.

Traumatic Brain Injury: Disruption of energy balance and ion homeostasis following traumatic brain injury (TBI), likewise, initiates a cascade of inflammation, excitotoxicity and oxidative stress that exacerbates acute brain tissue trauma.

Hibernation: Several species of mammals (eg. Ground squirrels and hamsters) hibernate as a way to survive extended periods of scarce food supply. Over the course of the hibernation season, torpor (a comatose-like state characterized by extreme decreases in body temperature, heart rate, blood flow and oxygen consumption) is interrupted at periodic intervals when animals spontaneously re-warm to 37^o C about every 5 to 14 days. These short periods of warm body temperature last 24-48 hrs. During repeated entry and exit from torpor hibernating animals titrate energy demand to meet energy supply such that energy balance is maintained even though blood flow, oxygen and glucose delivery plummet by as much as 90%.  Study of a natural genetic model adapted to dramatic fluctuations in energy supply and demand  (i.e., hibernation and arousal from hibernation) may point research towards alternative therapeutic strategies including novel agents and combination therapies for stroke, neurodegenerative disease and CNS trauma.

Several physiological changes associated with hibernation are consistent with tolerance to extremely low blood flow.  These include dramatic hypothermia, increased clotting times and decreased leukocyte counts, all of which we find in arctic ground squirrels.  Another change during hibernation that is consistent with neuroprotection is a profound increase in circulating ascorbate concentrations. One hypothesis we are currently investigating is that ascorbate protects the brain from oxidative stress during frequent, periodic arousal from hibernation (Drew et. al., 1999; Toein et al., 2001; see Science News article).