Browsing Chemistry and Biochemistry by Subject "Metabolism"
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Methods of temperature & metabolism reduction in rats and possible influence on human healthSpaceflight poses unique and significant hazards; the maintenance of human health remains a large part of the National Aeronautic and Space Administration (NASA) strategic goals and work remains to be done if we wish to maintain a long-term presence in space. The effects of ionizing radiation and bone density loss are some of the primary health related problems which need to be addressed. One of the main purposes of this research is to translate aspects of thermoregulation and metabolism reduction in hibernating species to a non-hibernating species in- order to devise alternative methods of preventing DNA damage and loss of bone density in astronauts. A second purpose for this research applies the same approach in emergency medicine, having potential as conjunctive therapy for cardiac arrest victims. Targeted temperature management (TTM; formerly known as therapeutic hypothermia) is the standard of care for these patients and is applied to increase survival rates and reduces neurological deficit. Stimulating Central Nervous System (CNS) A1 adenosine receptors inhibits shivering and non-shivering thermogenesis, inducing a hibernation-like response in hibernating species. A similar phenomenon occurs when using this technique in non-hibernating species such as rats. The adenosine A1 agonist, N6-cyclohexyladenosine (CHA) was utilized in all 3 of the experiments to determine how dose, diet, ambient temperature, and finally surface temperature affects the thermoregulatory response in Sprague-dawley rats. In addition to CHA, the partial agonist capadenoson was also tested for thermolytic efficacy (that is, the efficacy to abolish thermogenesis). Surface temperature control using a temperature controlled cage designed and built by myself in combination with IV CHA was found to be most effective in maintaining a target temperature of 32°C without risk of over-cooling. Results from these experiments suggests that the new standard technique in studying TTM using small animals should be similar to what is currently used in clinics; surface temperature modulation.
Modulation of ischemia- reperfusion injury in mammalian hibernators and non-hibernators: a comparative studyEvents 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.