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

描述(申请人提供)：每年发生100多万例创伤性脑损伤(TBI)，但目前还没有临床上有效的治疗方法来防止神经元丢失和增强行为功能。对CRISP数据库(1972-2004)的检查发现，只有两项由NIH赞助的拨款用于老年人的脑外伤！显然，我们需要的是一种安全、易于管理的药物，能够促进脑和脊髓损伤患者一生中的形态和行为恢复。埃默里大学目前正在进行一项治疗中重度钝性头部创伤的I/II期临床试验，它是一种很有前途的药物，它是神经类固醇孕酮。在我们之前的研究中，我们的实验室表明，在双侧额叶内侧皮质挫伤的大鼠中，短期的黄体酮注射可以减轻脑水肿，增强神经元的保护，并改善认知、感觉和运动功能。尽管孕酮被认为足够有效，足以保证临床测试，但关于它及其相关的前体和代谢物如何影响老年动物的功能和形态恢复，仍有许多需要了解。TBI的研究主要集中在儿童和年轻人身上，但对于老年人来说，这也是一个实质性的问题，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)使用剂量-反应范式中的行为分析，我们将检查黄体酮治疗对衰老和年轻成年雄性和雌性实验大鼠的功能影响。(2)在确定孕酮减少促炎基因的表达后，我们将使用免疫细胞化学(ICC)和分子生物学技术来研究这种类固醇如何影响由基因产生的炎症蛋白的水平，以及这些物质的减少如何影响成年和老年动物脑损伤后的水肿和免疫细胞侵袭。(3)由于人工合成的孕酮可广泛用于人类，在临床实践中经常被替代为天然孕酮(NPROG)，我们将比较nPROG和甲羟孕酮(MPA)的有效性和作用机制，后者是一种合成分子，具有与孕酮本身不同的受体和细胞作用。

DESCRIPTION (provided by applicant): Over a million cases of traumatic brain injury (TBI) occur each year, yet at present there are no clinically effective 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 previous 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 improve 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 treatments 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 effectiveness 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.