Combined Hypothermia and Neuroprotectants Extend Their Usefulness and Efficacy

描述(由申请人提供)： 这项修订后的翻译赠款申请寻求支持核心假设，即创伤后低温的使用不仅提供了初级神经元和血管保护，而且还延长了治疗窗口，在此期间，以前被确定为在损伤早期阶段具有神经保护作用的其他治疗方法获得了增强的疗效。尽管到目前为止，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。这一失败与这样一个事实有关，即在临床试验中，这些药物在创伤后过程中使用得太晚，无法起到明显的保护作用。目前的应用是围绕这样一个中心前提进行的，即使用轻度创伤后低温干预不仅可以增强脑和血管保护，还可以延长治疗窗口，在此窗口内可以使用其他保护剂以提高疗效。拟议的研究是基于初步数据，这些数据说明了这一假设在脑创伤动物中的可信度。此外，拟议的研究与NIH资助的一项正在进行的临床试验的设计相结合，该试验也在评估早期亚低温干预的效果。建议的研究将在流体冲击性脑损伤的大鼠和微型猪身上进行。33℃低温干预对脑外伤受损的脑血管反应性的影响将通过通过颅窗进行的功能研究来评估，同时评估不同脑白质区域和束的轴突损伤。此外，在啮齿类动物中，将进行认知评估。除了使用低温干预外，我们还将使用亚低温联合治疗，再加上延迟使用以前被认为只在超早期损伤后才具有保护作用的其他药物。为此，超氧化物歧化酶和免疫亲和素配体FK506和环孢菌素A将被使用，这是基于广泛的实验室数据，说明它们在脑损伤中的有效性，以及环孢菌素A目前也正在进行多中心临床试验的评估。如果成功，预计这些研究将被转化为全面的转化性研究，研究这些策略对多种创伤诱导的中枢神经系统异常的保护作用，同时还将考虑更多先前已确定的神经保护药物。这项申请与公共卫生直接相关。在创伤性脑损伤后使用低温的实验范式与正在进行的在脑外伤患者中进行的重要临床试验平行。此外，如果像假设的那样，低温的使用也延长了其他神经保护化合物保持疗效的治疗窗口，这项研究的结果可能具有更直接的临床意义。

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.