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，也是对退伍军人健康的主要威胁。 根据一项全国性的调查，每1,000名退伍军人中就有1-2名中风患者。不幸的是，到目前为止，对中风患者的有效治疗方法很少。大多数先前和当前的缺血性中风的实验性治疗集中于影响一种信号传导途径，调节单个膜蛋白/通道/受体如NMDA受体或靶向一种类型的细胞死亡机制如细胞凋亡。近年来，许多使用这些方法的临床试验的失败已经产生了共识，即复杂CNS疾病（如脑缺血）的有效治疗必须对多种途径和多种细胞类型具有压倒性的保护作用。到目前为止，还没有一种治疗急性中风患者的真正多方面和临床可行的方法。然而，一种潜在的治疗方法因其对大脑，心脏和大脑的多功能保护作用而脱颖而出。 其他器官：低温疗法。在动物和人体研究中，轻度至中度低温对脑缺血显示出显著的神经保护作用（高达90%的梗死减少）。另一方面，可用的物理手段的冷却技术是缓慢的（约3小时）并且不实用，这阻碍了低温疗法对急性中风患者的临床应用。因此，长期以来一直在寻求可用于低温治疗的化合物用于临床治疗。 使用药物诱导的低温，预计即使是体温的小下降（1- 2 ℃）也应该防止有害的中风后高温，延迟缺血性损伤的进展，并随后延长其他干预措施的治疗窗口。我们开发了新型神经降压素衍生物，如ABS 201和ABS 601，可以通过血脑屏障诱导“调节性低温”，在30分钟内将身体和大脑温度降低3- 5 ℃，而不会引起颤抖。对大鼠和猴的全身研究、血液试验和尸检表明，这些化合物无毒性和不良反应。这些化合物的缺血后给药显著减弱缺血诱导的脑损伤。因此，这些化合物提供了一种新的药物诱导的低温疗法。在这项为期四年的研究中，我们将测试两个特定目标，重点关注该疗法的转化潜力。目的1将确定低温NT/ABS复合物的剂量-反应曲线和时间过程（冷却、维持和复温阶段）。然后，将对选定的化合物进行检查，以确定“全脑保护”对抗缺血性中风的新方法。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色物质中不同细胞（神经元和非神经元细胞）中不同类型的细胞死亡（凋亡和坏死）。治疗还应防止血脑桶的破坏，减轻脑水肿和出血。目的2将评估缺血性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。将在老龄大鼠中进行实验，以模拟最脆弱的退伍军人群体;将测试不同的缺血性卒中模型，以评价各种临床条件下的治疗。这项研究计划是多年来在基础和临床前研究方面合作的结果。本研究有望为开发新的脑保护药物提供有力的证据，并有助于将化学/药理学低温治疗转化为临床应用。 公共卫生相关性： 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。制定临床有效可行的 在治疗中，我们将使用我们的新型神经降压素衍生物在啮齿动物中风模型中测试由药物诱导的低温诱导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.