PROGESTERONE AFTER TRAUMATIC BRAIN INJURY

描述：本修订研究提案的长期目标是 确定孕酮介导神经元 创伤性脑损伤（TBI）的抢救和功能恢复;主要 35岁以下年轻人的死亡原因。这些发现将是 用于评价孕酮作为一种安全有效的治疗方法 对于TBI。孕酮最近被归类为神经类固醇，因为它 也在两种动物大脑中的星形胶质细胞和少突胶质细胞中合成 男性和女性，在那里它可能发挥其他作用，而不是性激素。 先前的研究已经表明，全身注射黄体酮， 实验室大鼠可以减少TBI的一些神经病理学后果， 并促进行为功能的恢复。预后治疗减少 当给药时，雄性和雌性动物均出现显著脑水肿。 受伤的24小时这是一种保护作用，可以导致 减少神经元死亡和改善功能结果。的首要目标 目前的建议是更好地了解生理机制， 孕酮介导其神经保护作用。我们提出了一系列 4目的使用体外和体内神经损伤模型来确定： (1)孕酮是否通过其特异性受体发挥作用。这将是 通过将激素与ORG 31710（一种已知的孕酮）共同给药进行研究， 受体拮抗剂，或用激动剂替代孕酮， 在TBI的体内和体外模型中代谢（R5020）;（2）如果，在 体外损伤模型，孕酮的短期神经保护作用 通过σ受体特异性介导;（3）如果孕酮会阻止 通过减少氧化应激引起的线粒体功能丧失， TBI的体内和体外模型;以及（4）如果孕酮将减少TBI的 TBI后发生的炎症免疫反应的破坏性方面。 体内和体外模型的结合将提供平行评价 孕酮的作用机制本文提出的研究将 有助于确定孕酮是否可以作为一种低成本，安全， 中枢神经系统损伤急性期的有效治疗剂。而且 详细评估孕酮的作用机制将提供一个 人工治疗的智能设计基础 大药厂

DESCRIPTION: The long-term goal of this revised research proposal is to determine the specific mechanisms by which progesterone mediates neuronal rescue and recovery of function in traumatic brain injury (TBI); the major cause of death in young adults under the age of 35. These findings will be employed in the evaluation of progesterone as a safe and effective treatment for TBI. Progesterone has recently been classified as a neurosteroid because it is also synthesized in astrocytes and oligodendrocytes in the brains of both males and female, where it may play other roles than that of a sex hormone. Previous research has already shown that systemic injection of progesterone in laboratory rats can reduce some of the neuropathological consequences of TBI and enhance behavioral recovery of function. Progesterone treatments reduce cerebral edema dramatically in both males and females when administered within 24 hours of the injury. This is one type of protective effect that can lead to reduced neuronal death and improved functional outcomes. The primary goal of the current proposal is to understand better the physiological mechanisms by which progesterone mediates its neuroprotective actions. We propose a series of 4 Aims using both in vitro and in vivo models of neural injury to determine: (1) if progesterone exerts its effects via its specific receptors. This will be studied by co-administering the hormone with ORG31710, a known progesterone receptor antagonist, or substituting progesterone with an agonist that cannot be metabolized (R5020) in both in vivo and in vitro models of TBI; (2) if, in an in vitro model of injury, progesterone's short-term neuroprotective effects are mediated specifically via sigma receptors; (3) if progesterone will prevent loss of mitochondrial function by reducing oxidative stress initiated in both in vivo and in vitro models of TBI; and (4) if progesterone will reduce the destructive aspects of the inflammatory immune reaction that occurs after TBI. The combination of in vivo and in vitro models will provide parallel evaluation of the mechanisms of progesterone's action. The research proposed here will help to determine whether progesterone can be used as a low-cost, safe and effective therapeutic agent in the acute stages of CNS injury. Furthermore, the detailed assessment of progesterone's mechanisms of action will provide a foundation for the intelligent design of artificial therapeutic pharmaceuticals.