PROGESTERONE, TBI AND CNS REPAIR IN MATURE & AGED RATS.

每年发生100多万例创伤性脑损伤，但目前尚无临床救治病例。 预防神经元丢失和增强行为功能的有效治疗。一种清脆的检验 数据库(1972-2004)发现，只有两项由美国国立卫生研究院赞助的赠款用于治疗老年人的脑外伤！很明显的是 需要一种安全、易于管理的药物，可以促进大脑的形态和行为恢复 以及终生的脊髓损伤。目前在埃默里大学接受测试的一名有前途的特工 I/II期临床试验为中至重度钝性头部创伤，为神经类固醇黄体酮。在我们的Pre- 以前的研究，其中这个修订的建议是一个扩展，我们的实验室表明，短期的 大鼠损伤后注射孕酮可减轻脑水肿，增强神经元的保护作用，并促进脑缺血再灌注损伤。 证实双侧额叶内侧皮质挫伤大鼠的认知、感觉和运动功能。 尽管黄体酮被认为足够有效，足以保证临床试验，但仍有许多东西需要学习 关于它及其相关前体和代谢物如何影响老年人的功能和形态恢复 动物。TBI的大部分研究集中在儿童和年轻人身上，但它也是一个实质性的问题 老年人，他们经常因跌倒和事故而严重脑损伤！我们在这里的具体目标是：(1)使用 行为分析在剂量-反应范式中，我们将检查黄体酮治疗的功能影响- 在衰老和年轻的成年雄性和雌性实验大鼠身上。(2)在确定黄体酮 减少促炎基因的表达，我们将使用免疫细胞化学(ICC)和分子 用生物技术来研究这种类固醇如何影响由 基因，以及这些物质的减少如何影响脑外伤后的水肿和免疫细胞侵袭 成年和老年动物。(3)因为合成形式的黄体酮广泛可供人类使用，以及 在临床实践中经常被替换为自然孕酮(NPROG)，我们将比较其有效性- NPROG与人工合成分子醋酸甲羟孕酮的NSS及作用机制 它的受体和细胞作用可能不同于黄体酮本身。

Over a million cases of traumatic brain injury (TBI) occur each year, yet at present there are no clinically ef- fective treatments to prevent neuronal loss and enhance behavioral functions. An examination of the CRISP database (1972-2004) found only two NIH-sponsored grants addressing TBI in the elderly! What is clearly needed is a safe, easy-to-administer agent that can promote morphological and behavioral recovery in brain and spinal cord injuries across the life span. A promising agent currently under test at Emory University in a phase I/II clinical trial for moderate to severe blunt head trauma, is the neurosteroid progesterone. In our pre- vious research, of which this revised proposal is an extension, our laboratory showed that a short course of post-injury progesterone injections in rats could reduce cerebral edema, enhance neuronal sparing, and im- prove cognitive, sensory and motor functions in rats with bilateral contusions of the medial frontal cortex. Although progesterone was deemed effective enough to warrant clinical testing, there is still much to learn about how it, and its related precursors and metabolites, affect functional and morphological recovery in old animals. The bulk of TBI research focuses on children and young adults, but it is also a substantive issue for the elderly, who are often seriously brain-injured by falls and accidents! Our specific aims here are: (1) Using behavioral assays in a dose-response paradigm, we will examine the functional effects of progesterone treat- ments in senescent and young adult male and female laboratory rats. (2) Having determined that progesterone reduces the expression of pro-inflammatory genes, we will use immunocytochemical (ICC) and molecular biological techniques to investigate how this steroid affects the level of inflammatory proteins made by the genes, and how the reduction of these substances affects edema and immune cell invasion after TBI in both adult and old animals. (3) Because synthetic forms of progesterone are widely available for human use and are often interchanged for natural progesterone (nPROG) in clinical practice, we will compare the effective- ness and mechanisms of action of nPROG with medroxyprogesterone acetate (MPA), a synthetic molecule which has receptor and cellular actions that can be different from those of progesterone itself.