Combined Hypothermia and Neuroprotectants Extend Their Usefulness and Efficacy

描述（由申请人提供）： 这项修正的翻译资助申请寻求支持，以追求中心假设，即使用创伤后低温不仅提供主要的神经元和血管保护，而且还扩展了治疗窗口，其他疗法，以前确定为在损伤的早期阶段具有神经保护作用，获得增强的疗效。尽管迄今为止，在实验室中已经确定了许多成功的治疗策略来治疗创伤性脑损伤（TBI），但它们尚未证明在脑损伤的人类中有效。这种失败与以下事实有关：在临床试验中，这些药物在创伤后过程中给药太晚，无法发挥显著的保护作用。目前的申请是围绕中心前提的智力框架，即使用轻度创伤后低温干预不仅提供了增强的脑和血管保护，而且还扩展了治疗窗口，在该窗口内，可以使用其他保护剂以增强功效。拟议的研究是基于初步的数据，说明这一前提的可信度在创伤性脑损伤的动物。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，该临床试验也评估了早期轻度低温干预的有效性。拟定的研究将在遭受液压冲击脑损伤的大鼠和小型猪中进行。33的影响将通过经颅窗进行的功能研究评估TBI受损脑血管反应性的低温干预，同时评估不同脑白色物质区域和束中的轴突损伤。此外，将在啮齿动物中进行认知评估。除了使用低温干预，我们还将采用联合治疗，使用轻度低温，再加上延迟使用其他药物，以前被认为是保护只有超早期伤后。为此，超氧化物歧化酶和亲免素配体FK506和环孢菌素A将根据广泛的实验室数据使用，这些数据表明它们在TBI中的有用性，并且环孢菌素A目前也正在多中心临床试验中进行评估。如果成功，预计这些研究将转化为全面的转化研究，检查这些策略对多种创伤诱导的CNS异常的保护作用，同时考虑更大范围的先前确定的神经保护药物。这一应用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例与正在创伤性脑损伤的人中进行的重要临床试验平行。此外，如果如假设的那样，低温的使用也延长了其他神经保护化合物保持其功效的治疗窗口，则本研究的发现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.