Restricted diet and adenosine receptor activation: Therapy for brain ischemia

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DESCRIPTION (provided by applicant): Out-of-hospital cardiac arrest (CA) affects more than 300,000 people annually in the United States, with morbidity and mortality rates that have not improved in 50 years. Therapeutic hypothermia is currently the only treatment shown to improve prognosis in CA patients. Torpor as seen in hibernating animals has potential to decrease brain injury during global cerebral ischemia by suppressing metabolic demand. This project arises from a recent breakthrough finding that activation of sensitized A1 adenosine receptors (A1AR) is sufficient to induce torpor in the arctic ground squirrel (AGS; Spermophilus parryii). Preliminary data show that a similar phenomenon of metabolic suppression can be mimicked in rats fed a restricted diet. The proposed studies will examine the potential role of central adenosine receptors in mediating the metabolism suppressing effect of dietary restriction (DR). We will then ask if DR suppression of metabolism occurs independently of its reduction of body temperature. Finally, we will ask if DR protects the brain against injury following global ischemia. PUBLIC HEALTH RELEVANCE: The only therapy currently available for Out-of-Hospital Cardiac Arrest (CA) is hypothermia, which is thought to work in part by suppressing metabolism and hence the brain's need for oxygen. However, therapeutic hypothermia is complicated by untoward side-effects associated with cooling. The present research explores mechanisms used naturally in hibernating animals to suppress metabolism and the potential clinical utility of these mechanisms as prophylactic treatment for CA.