Combined Hypothermia and Neuroprotectants Extend Their Usefulness and Efficacy

低温疗法和神经保护剂相结合可扩展其用途和功效

• 批准号: 7470819
• 负责人: John T Povlishock
• 金额: $ 16.3万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470819
• 关键词: Address; Animals; Applications Grants; Axon; Behavior assessment; Behavioral; Blood Vessels; Brain; Brain Injuries; Cell Death; Cell Volumes; Cell physiology; Central Nervous System Diseases; Cephalic; Cerebrum; Chronic; Clinical; Clinical Trials; Cognitive; Communities; Complex; Coupled; Cyclosporine; Data; Electrophysiology (science); End Point; Endothelial Cells; FK506; Failure; Family suidae; Feeling hopeless; Funding; Healthcare; Hour; Human; Immunophilins; Injury; Intervention; Laboratories; Laboratory Study; Ligands; Link; Liquid substance; Mediating; Microcirculation; Modeling; Muscle function; N-Methylaspartate; Neurons; Neuroprotective Agents; Numbers; Other Therapy; Outcome; Patients; Peptidylprolyl Isomerase; Percussion; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Production; Protective Agents; Public Health; Rattus; Reactive Oxygen Species; Rodent; Rodent Model; Staging; Superoxide Dismutase; Superoxides; Sus scrofa; Therapeutic; Therapeutic Agents; Time; Topical application; Translating; Traumatic Brain Injury; Vascular Smooth Muscle; Week; base; clinically relevant; cost; design; desire; improved; inclusion criteria; injured; natural hypothermia; neuroprotection; pre-clinical; preclinical study; protective effect; response; translational study; white matter; young adult

DESCRIPTION (provided by applicant): This amended translational grant application seeks support to pursue the central hypothesis that the use of posttraumatic hypothermia not only provides primary neuronal and vascular protection, but also extends a therapeutic window over which other therapies, previously identified to be neuroprotective in the early phases of injury, gain enhanced efficacy. Although to date, many successful therapeutic strategies have been identified in the laboratory to treat traumatic brain injury (TBI), they have not proved efficacious in brain-injured humans. This failure has been linked to the fact that in clinical trials these agents were administered too late in the posttraumatic course to exert significant protection. The current application is intellectually framed around the central premise that the use of mild posttraumatic hypothermic intervention provides not only enhanced brain and vascular protection but also extends the therapeutic window over which other protective agents can be used with enhanced efficacy. The proposed studies are based upon preliminary data that speaks to the credibility of this premise in traumatically brain-injured animals. Further, the proposed studies are coupled to the design of an ongoing NIH-funded clinical trial that is also assessing the efficacy of early mild hypothermic intervention. The studies proposed will be conducted in rats and micropigs subjected to fluid percussion brain injury. The effects of 33¿C hypothermic intervention upon TBI-impaired cerebral vascular reactivity will be assessed through functional studies performed via cranial windows, with parallel assessments of axonal damage in various brain white matter regions and tracts. Further, in the rodents, cognitive assessments will be performed. In addition to the use of hypothermic intervention, we will also employ combinational therapy using mild hypothermia, coupled to the delayed use of other agents previously recognized to be protective only ultra early postinjury. To this end, superoxide dismutase and the immunophilin ligands, FK506 and cyclosporin A, will be used based upon extensive laboratory data speaking to their usefulness in TBI and the fact that cyclosporin A is also currently being assessed in multicenter clinical trials. If successful, it is anticipated that these studies will be translated into full blown translational studies examining the protective effects of these strategies on multiple traumatically induced CNS abnormalities, while also considering a larger array of previously identified neuroprotective drugs. This application has immediate relevance to public health. The experimental paradigm using hypothermia following traumatic brain injury parallels important clinical trials ongoing in traumatically brain-injured humans. Additionally, if as posited, the use of hypothermia also extends the therapeutic window over which other neuroprotective compounds retain their efficacy, the findings of this study may have even more immediate clinical relevance.

描述（由申请人提供）： 这项修改后的转化拨款申请寻求支持来追求一个中心假设，即使用创伤后低温不仅可以提供主要的神经元和血管保护，而且还可以扩展治疗窗口，使之前被认为在损伤早期具有神经保护作用的其他疗法，尽管迄今为止，实验室已经确定了许多成功的治疗策略来治疗创伤性脑损伤（TBI），但它们尚未被证明对脑损伤的人类有效。这种失败与临床试验中的事实有关。这些药物在创伤后病程中施用得太晚，无法发挥显着的保护作用，目前的应用是围绕这样的中心前提进行的：轻度创伤后低温干预的使用不仅可以增强大脑和血管的保护，而且还可以延长其他药物的治疗窗口。拟议的研究基于初步数据，证明了这一前提在脑外伤动物中的可信度。此外，拟议的研究与正在进行的 NIH 资助的临床试验的设计相结合。这也在评估早期轻度低温干预的功效将在遭受液体冲击脑损伤的大鼠和微型猪中进行 33¿对 TBI 损伤的脑血管反应性的低温干预将通过颅窗进行的功能研究进行评估，同时对各个大脑白质区域和束的轴突损伤进行平行评估。此外，还将在啮齿类动物中进行认知评估。除了使用低温干预外，我们还将采用轻度低温的联合治疗，同时延迟使用先前认为仅在受伤后超早期才具有保护作用的其他药物。亲免素配体 FK506 和环孢菌素 A 的使用将基于广泛的实验室数据，这些数据说明了它们在 TBI 中的有效性，并且环孢菌素 A 目前也在多中心临床试验中进行评估。如果成功，预计这些研究将会成功。可以转化为全面的转化研究，检查这些策略对多种创伤性中枢神经系统异常的保护作用，同时还考虑了更多先前确定的神经保护药物。该应用与公共健康直接相关。创伤性脑损伤后使用低温的实验范式与在创伤性脑损伤的人类中正在进行的重要临床试验相似。此外，如果如所假设的那样，低温的使用还可以延长其他神经保护化合物保留其功效的治疗窗口。可能具有更直接的临床意义。