Protection of the Brain by Chemical Hypothermia

描述(由申请人提供)： 中风是美国人类死亡的第三大原因，也是对退伍军人的主要健康威胁。根据一项全国性调查，每1000名退伍军人中有1-2名中风患者。不幸的是，到目前为止，对中风患者有效的治疗方法很少。以往和目前对缺血性中风的实验治疗大多集中在影响一条信号通路，调节单个膜蛋白/通道/受体，如NMDA受体，或针对一种类型的细胞死亡机制，如细胞凋亡。近年来，使用这些方法的许多临床试验的失败已经形成了一种共识，即对脑缺血等复杂的中枢神经系统疾病的有效治疗必须对多途径和多种细胞类型具有压倒性的保护作用。到目前为止，还没有真正多方面的、临床上可行的治疗急性中风患者的方法。然而，一种潜在的治疗方法因其对大脑、心脏和心脏的多种保护作用而引人注目。 其他器官：低温治疗。在动物和人类研究中，亚低温对脑缺血显示了显著的神经保护作用(高达90%的梗死灶减少)。另一方面，现有的物理降温技术缓慢(3小时)且不实用，这阻碍了亚低温治疗在急性卒中患者中的临床应用。因此，可用于低温治疗的化合物长期以来一直被寻求用于临床治疗。利用药物诱导的低温，即使是微小的体温下降(1-20摄氏度)，也可以防止有害的卒中后体温过高，延缓缺血性损伤的演变，从而延长其他干预的治疗窗口。我们已经开发出新的神经降压素衍生物，如ABS201和ABS601，它们可以通过血脑屏障诱导“调节低温”，在？30分钟内将身体和大脑温度降低3-5摄氏度，而不会引起颤抖。对老鼠和猴子的系统研究、血液测试和身体解剖检查表明，这些化合物没有毒性和不良影响。缺血后给予这些化合物可显著减轻缺血引起的脑损伤。因此，这些化合物提供了一种新的药物诱导的低温治疗方法。在这项为期四年的研究中，我们将测试两个特定的目标，以专注于该疗法的翻译潜力。目的1将测定低温NT/ABS化合物的剂量-效应曲线和时间过程(冷却、维持和复温阶段)。然后，将对一种选定的化合物进行研究，以期找到一种新的方法，即“全球脑保护”，预防缺血性中风。我们将测试药物诱导的低温抑制多种损伤机制的想法。因此，它可以阻断灰质和白质中不同细胞(神经元和非神经元细胞)的不同类型的细胞死亡(凋亡和坏死)。治疗还应防止血脑桶破裂，减轻脑水肿和出血。目的2将评估缺血脑的结构完整性和长期功能恢复，这是有效治疗的最终目标。将在老龄大鼠身上进行实验，以模拟最脆弱的退伍军人群体；将测试不同的缺血性中风模型，以便在各种临床条件下评估该疗法。这项研究提案是几年来基础和临床前研究合作努力的结果。预计本研究将为开发一类新的全球脑保护药物提供令人信服的证据，并有助于将化学/药物低温疗法转化为临床应用。 公共卫生相关性： 叙事缺血性中风是美国人类死亡的第三大原因，也是对退伍军人老龄化人口的主要健康威胁。开发一种临床上有效和可行的 在治疗方面，我们将使用我们的新型神经降压素衍生物，在啮齿动物的中风模型中测试药物诱导的低温所产生的脑保护和功能益处。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of human death in the US and a major health threat to our Veterans. According to a national survey, there are 1-2 stroke patients for every 1,000 Veterans. Unfortunately, so far there are very few effective therapies for stroke patients. Most previous and current experimental treatments for ischemic stroke have focused on affecting one signaling pathway, regulating an individual membrane protein/channel/receptor such as NMDA receptor or targeting one type of cell death mechanism such as apoptosis. The failure of many clinical trials using these approaches in recent years have generated the consensus that an effective therapy for complicated CNS disorders such as cerebral ischemia must have overwhelming protective effects on multiple pathways and multiple cell types. So far, there has been no therapy that is truly multifaceted and clinically feasible for acute stroke patients. One potential therapy, however, stands out for its versatile protective effects on the brain, heart and other organs: hypothermia therapy. Mild-to-moderate hypothermia has shown remarkable neuroprotective effects (up to 90% infarct reduction) against brain ischemia in animal and human studies. On the other hand, available cooling techniques of physical means are slow (¿3 hrs) and not practical, which have hampered clinical applications of hypothermia therapy to acute stroke patients. Thus, chemical compounds that can be utilized for hypothermia therapy have long been sought for clinical treatments. Using drug-induced hypothermia, it is expected that even a small drop of body temperature (1-2oC) should prevent the detrimental post-stroke hyperthermia, delay the evolution of ischemic injury, and thereafter extend the therapeutic window for other interventions. We have developed novel neurotensin derivatives such as ABS201 and ABS601 that can pass through the blood brain barrier to induce "regulated hypothermia", reducing body and brain temperature by 3-5oC in ¿30 min without causing shivering. Systemic study, blood tests and autopsy examinations in rats and monkeys showed no toxic and adverse effects of these compounds. Post-ischemic administration of these compounds markedly attenuates ischemia-induced brain injury. These compounds thus provide a novel drug-induced hypothermia therapy. In this four year investigation, we will test two Specific Aims to focus on translational potential of the therapy. Aim 1 will determine the dose-response curves and time courses (cooling, maintaining and rewarming phases) of hypothermic NT/ABS compounds. A selected compound will then be examined for the novel approach of "global brain protection" against ischemic stroke. We will test the idea that drug-induced hypothermia suppresses multiple injurious mechanisms. As a result, it can block different types of cell death (apoptosis and necrosis) in different cells (neurons and non- neuronal cells) in gray and white matters. The treatment should also prevent disruption of the blood brain barrel, attenuate brain edema and hemorrhage. Aim 2 will evaluate structural integrity and long-term functional recovery of the ischemic brain, which is the ultimate goal of an effective therapy. Experiments will be performed in aging rats to mimic the most vulnerable population of Veterans; different ischemic stroke models will be tested in order to evaluate the therapy in a variety of clinical conditions. This research proposal is a result from several years of collaborative efforts in basic and preclinical investigations. It is expected that this research wll provide compelling evidence for developing a new category of global brain protection drugs and help to translate the chemical/pharmacological hypothermic therapy to clinical applications. PUBLIC HEALTH RELEVANCE: Narrative Ischemic stroke is the third leading cause of human death in the US and a major health threat to the aging population of Veterans. To develop a clinically effective and feasible therapy, we will test the brain protection and functional benefits induced by drug-induced hypothermia in stroke models of rodents using our novel neurotensin derivatives.