PROGESTERONE AFTER TRAUMATIC BRAIN INJURY

描述：修订后的研究提案的长期目标是 确定孕酮调节神经元的具体机制 创伤性脑损伤的抢救与功能恢复 35岁以下青壮年死因。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。黄体酮最近被归类为神经类固醇，因为它 也是在星形胶质细胞和少突胶质细胞中合成的 男性和女性，在那里它可能扮演着性激素以外的其他角色。 先前的研究已经表明，全身注射黄体酮对 实验大鼠可减轻脑外伤的部分神经病理后果 促进功能的行为恢复。黄体酮治疗可减少 男性和女性在以下情况下都会出现严重的脑水肿 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，改善功能结果。的主要目标是 目前的建议是通过以下方式更好地了解生理机制 哪种黄体酮是其神经保护作用的中介。我们提出了一系列 4旨在使用神经损伤的体外和体内模型来确定： (1)孕酮是否通过其特定受体发挥作用。这将是 通过与已知的黄体酮ORG31710共同给予激素进行研究 受体拮抗剂，或用不能 在体内和体外模型中被代谢(R5020)；(2)如果， 黄体酮短期神经保护作用的体外损伤模型 特异性地通过Sigma受体介导；(3)黄体酮是否能阻止 由减少氧化应激引起的线粒体功能的丧失 体内和体外脑损伤模型；(4)黄体酮是否会减少 创伤性脑损伤后炎性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的评估 黄体酮的作用机制。这里提出的研究将 帮助确定黄体酮是否可以作为一种低成本、安全和 中枢神经系统损伤急性期的有效治疗剂。此外， 对黄体酮作用机制的详细评估将提供 人工疗法智能化设计的基础 制药公司。

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.