The overall objectives of this proposal are to examine the influence of mild hyperthermia, mild hypothermia, and the induction of heat shock proteins, on global and focal cerebral ischemia. Our goal will be the development of therapeutic interventions (hypothermia, heat shock protein) for treatment of ischemic insult, as well as improvement of patient management by exploration of the role of fever in cerbral ischemia. The following series of specific aims are in accordance with the overall objectives. 1) To invesitgate the effects of mild, whole body, and local cerebral hyperthermia (40 degrees C < T < 41 degrees C) on cerebral ischemia (globe and focal). Hypotheses: Mild hyperthermia has a detrimental effect on the outcome of an episode of transient global ischemia or focal ischemia. 2) To investigate the effects of whole body hypothermia (T=35 degrees C, 27 degrees C) on cerebral ischemia (global and focal). Hypotheses: Mild whole body hypothermia when judiciously applied, has a beneficial effect on the outcome from an episode of cerebral ischemia. The beneficial effect may be acquired at low grade hypothermia (T=35 degrees C). The sequencing of hypothermia with respect of the ischemic insult is an important factor in affecting outcome. 3) To investigate the effects of the induction of thermotolerance and concomitant heat shock proteins on anoxia and glucose deprivation in Chines Hamster Ovary (CHO) and glioblastoma cells (in vitro), and on cerebral ischemia (in vivo). Hypotheses: Thermotolerant tissues and cells sustain metabolic insult, and are more tolerant to stress perturbations than normal tissue. Thermotolerance is associated with the induction of a family of stress proteins, also known as heat shock proteins (HSP). These proteins may play a role in protecting tissue for subsequent trauma and metabolic injury. The time course of high energy phosphate metabolites and intracellular pH will be measured using in vivo 31PNMR spectroscopy along with CBF, and neurological and histological garaging in all experiments.
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