Restricted diet and adenosine receptor activation: Therapy for brain ischemia

描述(由申请人提供)：院外心脏骤停(CA)在美国每年影响30多万人，其发病率和死亡率50年来没有改善。治疗性低温是目前唯一能改善CA患者预后的治疗方法。在冬眠动物中看到的麻木有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，即致敏的A1腺苷受体(A1AR)的激活足以引起北极地松鼠(AGS；Spermophilus parryii)的麻木。初步数据显示，在限制饮食的大鼠身上也可以模仿出类似的代谢抑制现象。这项拟议的研究将考察中枢腺苷受体在调节饮食限制(DR)的代谢抑制效应中的潜在作用。然后我们会问，DR对新陈代谢的抑制是否与其降低体温无关。最后，我们将询问DR是否保护大脑免受全球缺血后的损伤。 与公共卫生相关：目前可用于院外心脏骤停(CA)的唯一疗法是低温，它被认为在一定程度上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，治疗性低温因与降温相关的不良副作用而变得复杂。本研究探索了在冬眠动物中用于抑制代谢的自然机制，以及这些机制作为CA预防性治疗的潜在临床应用。

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.