Restricted diet and adenosine receptor activation: Therapy for brain ischemia

描述（由申请人提供）：在美国，院外心脏骤停（CA）每年影响超过30万人，发病率和死亡率在50年内没有改善。治疗性低温是目前唯一的治疗显示，以改善CA患者的预后。冬眠动物中出现的休眠状态可能通过抑制代谢需求来减少全脑缺血期间的脑损伤。该项目源于最近的一项突破性发现，即致敏A1腺苷受体（A1 AR）的激活足以诱导北极地松鼠（AGS; Spermophilus parryii）的麻痹。初步数据显示，在限制饮食的大鼠中可以模拟类似的代谢抑制现象。拟开展的研究将探讨中枢腺苷受体在介导饮食限制（DR）代谢抑制效应中的潜在作用。然后，我们将询问DR对代谢的抑制是否独立于其对体温的降低而发生。最后，我们将探讨DR是否能保护脑免受全脑缺血损伤。 公共卫生相关性：目前唯一可用于院外心脏骤停（CA）的治疗方法是低温，这被认为是通过抑制新陈代谢，从而抑制大脑对氧气的需求而起作用的。然而，治疗性低温由于与冷却相关的不良副作用而变得复杂。本研究探讨了冬眠动物中自然使用的抑制代谢的机制，以及这些机制作为CA预防性治疗的潜在临床用途。

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.