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

描述（申请人提供）：每年有超过一百万例的创伤性脑损伤（TBI）病例发生，但目前临床上还没有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）的一项检查发现，只有两项nih资助的针对老年人TBI的资助！显然，我们需要的是一种安全、易于管理的药物，可以促进大脑和脊髓损伤患者在整个生命周期内的形态和行为恢复。埃默里大学（Emory University）目前正在进行一项I/II期临床试验，用于治疗中度至重度钝性头部创伤，这是一种很有前景的药物，即神经类固醇黄体酮。在我们之前的研究中，我们的实验室表明，在双侧内侧额叶皮质挫伤的大鼠中，短时间的损伤后黄体酮注射可以减少脑水肿，增强神经元保留，改善认知、感觉和运动功能。虽然黄体酮被认为是有效的，足以保证临床试验，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，还有很多需要了解的。大部分的脑外伤研究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，老年人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)在确定黄体酮降低促炎基因的表达后，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这些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TBI后的水肿和免疫细胞入侵。(3)由于合成形式的黄体酮广泛用于人类使用，并且在临床实践中经常与天然黄体酮（nPROG）互换，我们将比较nPROG与醋酸甲羟黄体酮（MPA）的有效性和作用机制，醋酸甲羟黄体酮是一种合成分子，具有与黄体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.