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）： 中风是美国人类死亡的第三大主要原因，也是对退伍军人的重大健康威胁。根据全国调查，每1,000名退伍军人有1-2名中风患者。不幸的是，到目前为止，中风患者的有效疗法很少。缺血性中风的大多数先前和当前的实验治疗都集中在影响一个信号通路上，调节单个膜蛋白/通道/受体（例如NMDA受体）或靶向一种细胞死亡机制，例如细胞凋亡。近年来，许多使用这些方法的临床试验的失败产生了共识，即对复杂的中枢神经系统疾病（例如脑缺血）进行有效的治疗，必须对多种途径和多种细胞类型产生压倒性的保护作用。到目前为止，尚无对急性中风患者的真正多方面且在临床上可行的疗法。然而，一种潜在的疗法因其对大脑，心脏和心脏的多才多艺影响而脱颖而出 其他器官：体温过低。在动物和人类研究中，轻度至中度的体温过低表现出明显的神经保护作用（降低了90％的梗塞减少））。另一方面，物理手段的可用冷却技术是缓慢的（3小时）而不是实用的，这阻碍了体温过低治疗对急性中风患者的临床应用。这是，可以用于低温治疗的化合物已经很长时间了，我们已经开发了新型的神经素衍生物，例如ABS201和ABS601，它们可以通过血脑屏障，以诱导“调节的低温下降”，在30分钟内诱导3-5oC诱导身体和脑温度，而不会引起分解。在大鼠和猴子中进行的全身研究，血液检查和尸检检查显示这些化合物没有毒性和不良影响。这些化合物的缺血后给药显着减弱缺血引起的脑损伤。因此，这些化合物提供了一种新型的药物诱导的体温过低疗法。在这四年的调查中，我们将测试两个具体目的，以专注于疗法的翻译潜力。 AIM 1将确定低温NT/ABS化合物的剂量反应曲线和时间疗程（冷却，维持和重新加热阶段）。然后，将检查选定的化合物，以针对缺血性中风的“全球脑保护”的新方法进行检查。我们将测试药物诱导的体温过低会抑制多种有害机制的观念。结果，它可以阻止灰色和白质的不同细胞（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）。治疗还应防止血液桶的破坏，减轻脑水肿和出血。 AIM 2将评估缺血性大脑的结构完整性和长期功能恢复，这是有效疗法的最终目标。实验将在老化的大鼠中进行，以模仿最脆弱的退伍军人人口；将测试不同的缺血性中风模型，以评估在各种临床条件下的治疗。这项研究建议是基本和临床前研究的几年合作努力的结果。可以预期，这项研究为开发新的全球脑保护药物提供了令人信服的证据，并有助于将化学/药理低温治疗转化为临床应用。