Protection of the Brain by Chemical Hypothermia

化学低温保护大脑

• 批准号: 8998977
• 负责人: Shan P. Yu
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998977
• 关键词: Adverse effects; Affect; African American; Age; Aging; Agonist; Alteplase; American; Animal Model; Animals; Apoptosis; Attenuated; Autopsy; Behavior; Blood; Blood - brain barrier anatomy; Blood Tests; Blood flow; Body Temperature; Brain; Brain Edema; Brain Injuries; Brain Ischemia; Brain hemorrhage; Categories; Caucasians; Cause of Death; Cell Death; Cells; Central Nervous System Diseases; Cerebral Ischemia; Cessation of life; Chemicals; Clinical; Clinical Treatment; Clinical Trials; Consensus; Data; Dose; Drops; Drug usage; Dyes; Elderly; Epidemiology; Evolution; FDA approved; Failure; General Anesthesia; Goals; Guidelines; Health; Heart; Human; Hyperthermia; Hypothalamic structure; Image; Incidence; Individual; Infarction; Injury; Intervention; Investigation; Ischemia; Ischemic Stroke; Knockout Mice; Magnetic Resonance Imaging; Measures; Membrane Proteins; Methods; Modeling; Monkeys; Mus; N-Methyl-D-Aspartate Receptors; Necrosis; Neuroglia; Neurologic; Neurons; Neurotensin; Organ; Outcome; Pathway interactions; Patients; Peptide Synthesis; Pharmaceutical Preparations; Phase; Population; Process; Publishing; Rattus; Recovery of Function; Reperfusion Injury; Research; Research Proposals; Rewarming; Rodent; Rodent Model; Shivering; Signal Pathway; Slice; Staining method; Stains; Stroke; Structural Models; Surveys; Techniques; Temperature; Testing; Therapeutic; Time; Toxic effect; Translating; Translational Research; Traumatic Brain Injury; United States; Veterans; Vibrissae; Vulnerable Populations; acute stroke; age group; aging population; barrel cortex; blood flow measurement; brain tissue; cell type; clinical application; cognitive function; disability; drug development; drug testing; effective therapy; gray matter; human old age (65+); improved; in vivo; induced hypothermia; middle age; natural hypothermia; novel; novel strategies; optical imaging; post stroke; pre-clinical; prevent; protective effect; receptor; research study; response; restoration; vasoconstriction; white matter

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.

描述（由申请人提供）： 中风是美国第三大人类死亡原因，也是退伍军人的主要健康威胁。根据一项全国调查，每 1,000 名退伍军人中就有 1-2 名中风患者，但迄今为止，有效的治疗方法很少。大多数先前和当前针对缺血性中风的实验性治疗都集中在影响一种信号通路、调节单个膜蛋白/通道/受体（例如NMDA受体）或针对一种类型的细胞死亡机制（例如细胞凋亡）。试验使用近年来，这些方法已达成共识，即针对脑缺血等复杂中枢神经系统疾病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，迄今为止，还没有真正多方面且临床可行的治疗方法。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：低温治疗在动物和人类研究中显示出显着的神经保护作用（最多可减少 90% 的梗塞）。小时）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找可用于低温疗法的化合物用于临床治疗。体温过低，预计即使体温小幅下降（1-2oC）也能预防中风后高热的困扰，延缓缺血性损伤的进展，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。例如ABS201和ABS601可以穿过血脑屏障，引起“调节性低温”，在30分钟内将身体和大脑温度降低3-5℃，导致不发抖。对大鼠和猴子的系统研究、血液测试和尸检显示，这些化合物在缺血后施用没有显着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疗法。在这第四年的研究中，我们将测试两个具体目标，重点关注治疗的转化潜力，目标 1 将确定剂量反应曲线和时间进程（降温、维持和复温阶段）。然后，我们将测试一种选定的化合物是否具有预防缺血性中风的“全局脑保护”的新方法，即药物引起的低温可以抑制多种损伤机制。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的破坏，减轻脑水肿。目标 2 将评估缺血性大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。将在衰老大鼠中进行实验，以模拟最脆弱的退伍军人群体；将进行测试，以评估各种临床条件下的治疗。这项研究提案是多年基础和临床前研究合作努力的结果，预计这项研究将为开发新类别提供令人信服的证据。全球大脑保护帮助化学药物/药理低温疗法转化为临床应用。