Targeting Central A1 Adenosine Receptors Induces Hypothermia for Stroke

描述(申请人提供)：轻度治疗低温可以改善从心脏骤停复苏的患者的预后，但对中风患者并没有显示出好处。中风的疗效较差，部分原因可能是难以为清醒的患者降温。在这里，我们建议通过激活脑A1腺苷受体(A1AR)来诱导中风啮齿动物模型的治疗性低温，这是冬眠哺乳动物在冬眠开始时用来降低体温的一种机制。我们将使用遥测和其他技术来测试A1AR激动剂6N-环己基腺苷(CHA)诱导的轻中度治疗低温的安全性和有效性，以监测清醒、自由活动的大鼠降温和复温期间的脑温、心电图、血压和其他生理参数。我们将尝试使用8-(对磺苯基)茶碱(8-SPT)，一种不能穿透大脑的腺苷受体拮抗剂，来阻止刺激心脏和其他外周器官的A1AR所引起的不良反应。我们还将研究这种方法在缺血性中风大鼠模型中诱导治疗性低温的安全性和有效性。初步数据显示，在环境温度为16摄氏度的情况下，间歇性腹腔注射CHA和8-SPT可使大鼠的核心体温保持在30至32摄氏度之间24小时，而不会出现不良后果。这种创新的降温方法模仿了冬眠动物降温到接近环境温度的机制，避免了颤抖的负面影响。在绕过发抖等体温调节防御方面，这项研究具有非常重要的意义，因为它可能会改进用于诱导治疗性低体温的技术，这可能对中风患者有重大好处。与此同时，这一应用程序在阿拉斯加大学费尔班克斯大学建立了生物医学研究基础设施，并为阿拉斯加学生带来了生物医学研究机会，包括一批在生物医学研究中代表性不足的有才华的阿拉斯加原住民学生。

DESCRIPTION (provided by applicant): Mild therapeutic hypothermia improves outcome for patients resuscitated from cardiac arrest but has failed to show benefit for stroke patients. Poor efficacy in stroke is likely due in part to the difficulty of cooling conscious patients. Here we propose to induce therapeutic hypothermia in a rodent model of stroke via activation of brain A1 adenosine receptors (A1AR), a mechanism used by hibernating mammals to decrease body temperature during onset of hibernation. We will test the safety and efficacy of mild to moderate therapeutic hypothermia induced by the A1AR agonist 6N-cyclohexyladenosine (CHA) using telemetry and other techniques to monitor brain temperature, ECG, blood pressure and other physiological parameters during cooling and rewarming in conscious, freely moving rats. We will attempt to block adverse effects caused by stimulation of A1AR in the heart and other peripheral organs using 8-(p-sulfophenyl) theophylline (8-SPT), an adenosine receptor antagonist that does not penetrate the brain. We will also study the safety and efficacy of this approach to induce therapeutic hypothermia in a rat model of ischemic stroke. Preliminary data show that intermittent intraperitoneal injections of CHA and 8-SPT at an ambient temperature of 16oC maintain core body temperature between 30 and 32oC for 24h in rats without adverse consequences. This innovative approach to cooling mimics the mechanism used by hibernating animals to cool to near-ambient temperature and avoids the negative effects of shivering. In bypassing thermoregulatory defenses such as shivering, this research is highly significant because it is likely to refine techniques used to induce therapeutic hypothermia that may have significant benefit for stroke patients. At the same time, this application builds biomedical research infrastructure at the University of Alaska Fairbanks and brings biomedical research opportunities to Alaskan students, including a population of talented Alaska Native students who are underrepresented in biomedical research.