Stroke Treatment by Chemically-Induced Hypothermia

描述（由申请人提供）： 中风是美国第三大死亡原因。尽管进行了深入的研究，但治疗急性卒中患者的临床治疗仍然有限且不令人满意。有一致的动物和人体数据表明，轻度至中度低温（将体温降至32- 34 ℃）通常是安全的，并可改善脑缺血后的结果，即使在缺血发生数小时后开始。与大多数神经保护药物通常只针对一种机制不同，低温治疗具有对灰色和白色物质中的所有细胞类型和组织的全局保护的优点。然而，有几个重要的局限性阻碍了低温疗法在中风患者中的广泛应用。主要障碍是现有的“强制冷却”技术在临床环境中无效和/或不切实际。为了克服现有方法的缺点，通过药理学手段诱导的“调节性低温”的概念被提出作为低温治疗的新策略;尽管还没有可用于调节性低温治疗的药物。为此，我们合成并测试了新型神经降压素（NT）[8-13]衍生物，如ABS 201和ABS 601，它们是有效的低温化合物，在动物中风模型中具有显著的神经保护活性。这些NT化合物显示无毒性作用，即使在缺血发作后45分钟给药，也可使梗塞形成减少近50%。保护的机制似乎涉及它们穿过血脑屏障的能力，结合到NT受体作为激动剂，并降低中央温度控制的“设定点”，从而在没有颤抖的情况下促进全身体温降低。因此，假设NT/ABS衍生物具有很强的潜力被开发用于调节性低温治疗。在I期研究中，我们将比较六种NT/ABS衍生物的低温效力。两个领先的化合物没有检测到的副作用将测试和比较他们的神经保护在两个中风模型的短暂性和永久性缺血的老年大鼠。这种翻译研究并不打算描绘低温保护的机制，这是迄今为止已被广泛研究。相反，我们的目标是证明化学诱导的低温治疗的可行性，并进入更系统的临床前检查的第二阶段研究。我们的最终目标是将药物诱导的低温治疗推向临床。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States. In spite of intensive investigations, clinical therapies for treating acute stroke patients remain limited and unsatisfactory. There are consistent animal and human data that mild to moderate hypothermia (reducing body temperature to 32-34oC) is generally safe and improves outcome after brain ischemia even when initiated hours after ischemia occurs. Different from most neuroprotective drugs that usually target only one mechanism, hypothermia therapy has the advantage of global protection on all cell types and tissues in both gray and white matters. Several important limitations, however, have precluded the widespread use of hypothermia therapy in stroke patients. The major obstruction is that existing "forced cooling" techniques are ineffectual and/or impractical in clinical settings. To overcome the shortcomings of current methods, the concept of "regulated hypothermia" induced by pharmacological means has been proposed as a new strategy in hypothermia therapy; although there have been no drugs that can be used for regulated hypothermia therapy. To this end, we have synthesized and tested novel neurotensin(NT)[8-13] derivatives, such as ABS201 and ABS601, that are potent hypothermic compounds and have dramatic neuroprotective activity in animal stroke models. These NT compounds show no toxic effects, attenuate infarct formation by nearly 50% even when administered 45 min after the onset of ischemia. The mechanism of protection appears to involve their ability to cross the blood brain barrier, bind to the NT receptor as agonists, and reduce the "set point" of the central temperature control so that systemic hypothermia in the absence of shivering is promoted. It is thus hypothesized that NT/ABS derivatives have strong potential of being developed for regulated hypothermia therapy. In the Phase I study, we will compare the hypothermic potency of six NT/ABS derivatives. Two leading compounds without detectable side effects will be tested and compared for their neuroprotection in aged rats of two stroke models of transient and permanent ischemia. This translational investigation is not intended to delineate the mechanism of hypothermia protection, which has been extensively studied so far. Rather, we aim to demonstrate the feasibility of the chemical-induced hypothermia therapy and move to more systematic preclinical examinations of a Phase II investigation. Our ultimate goal is to advance the drug-induced hypothermia therapy to the clinic.