Modulation of ischemia- reperfusion injury in mammalian hibernators and non-hibernators: a comparative study

Abstract

Events characterized by ischemia/reperfusion (I/R), such as stroke and cardiac arrest, are among the most frequent causes of debilitating neurological injury and death worldwide. During ischemia, the brain experiences oxygen and nutrition deprivation due to lack of blood flow, and tissue damage ensues. Arctic ground squirrel (AGS; Urocitellus parryii), a hibernating species has the innate ability to survive profound decreases in blood flow (ischemia) during torpor and return of blood flow (reperfusion) during intermittent euthermic periods without any neurological deficit. However, the mechanisms by which AGS tolerate the extreme fluctuations in blood flow remain unclear. The main focus of this thesis is to investigate the modulation of I/R injury in mammalian hibernators and non-hibernators. The first study validates the microperfusion approach for studying in vitro I/R injury (oxygen glucose deprivation, OGD) modeled in acute hippocampal slices and investigates the complex interactions of glutamate-mediated excitotoxicity with acidosis-mediated acidotoxicity to understand the role of acid-sensing ion channels (ASIC1a) and pH in mediating cellular injury during OGD. Using an ischemic tolerant animal model, AGS, the second and third studies explore if hibernation season or state influences tolerance to I/R injury and tests hypotheses regarding mechanisms involving nitric oxide and superoxide radicals in mediating cellular damage during cerebral I/R. Together, this dissertation demonstrates that when OGD is combined with acidosis as occurs in vivo, acidotoxicity mediated via ASIC1a occurs but low pH abolishes NMDAR mediated excitotoxicity. This dissertation also presents evidence that AGS tolerate OGD injury independent of hibernation season and state. At the tissue level, when tissue temperature is normalized to 36°C despite ATP depletion, ionic derangement, tissue acidosis, and excitatory neurotransmitter efflux, AGS hippocampus resists OGD injury. Finally, the dissertation shows that AGS resist brain injury caused by ONOO- generated from NO or O2•− during OGD while rat brain tissue succumbs to this mechanism of injury.