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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Hicks, Ramona R
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Emory University
Emergency Medicine
Schools of Medicine
United States
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Hua, Fang; Reiss, Jenny I; Tang, Huiling et al. (2012) Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury. Horm Behav 61:642-51
Stein, Donald G; Cekic, Milos M (2011) Progesterone and vitamin d hormone as a biologic treatment of traumatic brain injury in the aged. PM R 3:S100-10
Cekic, Milos; Cutler, Sarah M; VanLandingham, Jacob W et al. (2011) Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging 32:864-74
Hua, Fang; Wang, Jun; Ishrat, Tauheed et al. (2011) Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J Neuroinflammation 8:42
Ishrat, Tauheed; Sayeed, Iqbal; Atif, Fahim et al. (2010) Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol 226:183-90
Cekic, Milos; Stein, Donald G (2010) Traumatic brain injury and aging: is a combination of progesterone and vitamin D hormone a simple solution to a complex problem? Neurotherapeutics 7:81-90
Ishrat, Tauheed; Sayeed, Iqbal; Atif, Fahim et al. (2009) Effects of progesterone administration on infarct volume and functional deficits following permanent focal cerebral ischemia in rats. Brain Res 1257:94-101
Kasturi, Badrinarayanan S; Stein, Donald G (2009) Progesterone decreases cortical and sub-cortical edema in young and aged ovariectomized rats with brain injury. Restor Neurol Neurosci 27:265-75
Kasturi, Badrinarayanan S; Stein, Donald G (2009) Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats. J Neurotrauma 26:1315-24
Hua, Fang; Wang, Jun; Sayeed, Iqbal et al. (2009) The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice. Biochem Biophys Res Commun 390:678-83

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