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. ? ?
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