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Wo 2010/088409 A2 (12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 5 August 2010 (05.08.2010) WO 2010/088409 A2 (51) International Patent Classification: Not classified AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2010/022433 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 28 January 2010 (28.01 .2010) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/148,8 14 30 January 2009 (30.01 .2009) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, EMORY UNIVERSITY [US/US]; 1599 Clifton Road, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, 4th Floor, Atlanta, GA 30322 (US). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (72) Inventor; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventor/Applicant (for US only): STEIN, Donald, G. ML, MR, NE, SN, TD, TG). [US/US]; 63 1 Kimberly Lane, Atlanta, GA 30306 (US). Published: (74) Agents: BRINCKERHOFF, Courtenay, C. et al; Foley & Lardner Lie, 3000 K Street Nw, Washington, DC — without international search report and to be republished 20007 (US). upon receipt of that report (Rule 48.2(g)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: METHODS OF NEUROPROTECTION USING NEUROPROTECTIVE STEROIDS AND A VITAMIN D (57) Abstract: Described herein are compositions and FiGLRL 3 methods for treating or preventing nervous system injury. A n In particular, the methods and compositions relate to the use of at least one neuroprotective steroid, such as proges- j terone, and vitamin D. METHODS OF NEUROPROTECTION USING NEUROPROTECTIVE STEROIDS AND A VITAMIN D RELATED APPLICATIONS This application claims the priority benefits under 35 U.S .C. § 119(e) to U.S. provisional application 61/148,814, filed January 30, 2009, the entire contents of which are incorporated herein by reference. STATEMENT OF GOVERNMENT SUPPORT This invention was made using U.S. government funds under NIH grants #1R01N540825 and #1RO1N538664 and the government has certain rights in the invention. FIELD OF THE INVENTION The present invention is in the area of pharmaceutical chemistry and specifically relates to diagnostic methods and uses of vitamin D and analogs in combination or alternation with certain neuroprotective steroids in treatment of nervous system injury or nervous system inflammation related to injury or disease. Certain pharmaceutical compositions are also provided that allow enhanced recovery of neurological functions after inflammation or injury that include vitamin D in combination with certain steroid compounds, in particular progesterone or its active metabolites, prodrugs, and analogs. BACKGROUND OF THE INVENTION Brain injuries, including traumatic brain injury (TBI) and stroke, affect well over 2 million Americans each year and are a significant health concern worldwide. There are currently approximately 5.7 million stroke survivors in the US, many with permanent disabilities, and more than 5 million Americans who have suffered a TBI resulting in the permanent need for help in performing daily activities. Traumatic brain injuries result from a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain, with severity ranging from "mild," i.e., a brief change in mental status or consciousness to "severe," i.e., an extended period of unconsciousness or amnesia after the injury. In contrast, strokes are a result of diseases that affect the blood vessels that supply blood to the brain. A stroke occurs when a blood vessel that brings oxygen and nutrients to the brain cither bursts (hemorrhagic stroke) or is clogged by a blood clot or some other mass (ischemic stroke). The majority of strokes are ischemic, however hemorrhagic strokes typically result in more severe injuries. Despite several decades of effort, scientists have not yet found a pharmacological agent that consistently improves outcomes after brain injuries such as stroke or TBl (sec Sauerland, S. et a!., Lancet 2004, 364, 1291-1292; Brain Trauma Foundation, American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe head injury. J. Neurotrauma 1996, 13, 641-734). After TBI or stroke, inflammation is a primary cause of secondary damage and long - term damage. Following insults to the central nervous system, a cascade of physiological events leads to neuronal loss including, for example, an inflammatory immune response and excitotoxicity resulting from disrupting the glutamate, acetylcholine, cholinergic, GABAA, and NMDA receptor systems. In these cases, a complex cascade of events leads to the delivery of blood-borne leucocytes to sites of injury to kill potential pathogens and promote tissue repair. However, the powerful inflammatory response has the capacity to cause damage to normal tissue, and dysregulation of the innate, or acquired immune response is involved in different pathologies. In addition to TBI and stroke, inflammation is being recognized as a key component of a variety of nervous system disorders. It has long been known that certain diseases such as multiple sclerosis are due to inflammation in the central nervous system, but it is only in recent years that it has been suggested that inflammation may significantly contribute to neurodegenerative disoders such as HIV-related dementia, Alzheimer's and prion diseases. It is now known that the resident macrophages of the central nervous system (CNS), the microglia, when activated may secrete molecules that cause neuronal dysfunction, or degeneration. While TBI is a leading cause of death and disability among people of all ages in the United States, the rate of death from TBI has declined for most age groups over the past ten years due in large part to improved safety measures such as the use of safety belts. However, the rate of TBI in the elderly it has risen by over 21% (Langlois et al, 2004) and is currently more than twice that of the younger population (Mosenthal et ai, 2002). In addition, the risk of stroke increases with age. For each decade after age 55, the risk of stroke doubles and in each year, more than 70 percent of people who suffer a stroke are over the age of 65. In addition to higher incidence of neurological injuries and disorders, the elderly are also often subject to alterations in certain systemic hormonal levels that may significantly affect their response to injury (Topinkova, 2008). Aside from advanced age, itself a major predictor of injury severity, other potentially exacerbating factors in the aged include systemic issues such as kidney disease, hypertension, atherosclerosis and cardiovascular disease diabetes, cancer and hormonal imbalances such as hyperparathyroidism. While all of these conditions can affect responses to injury, each has also been associated in the growing literature with insufficient serum levels of vitamin D as often ignored underlying problem (Grant, 2006; Holick and Chen, 2008; Peterlik and Cross, 2005). Vitamin D is the term used for a group of fat-soluble prohormones, the two major forms of which are vitamin D (or ergocalciferol) and vitamin D3 (or cholecalciferol). The term "vitamin D" also refers to metabolites and other analogues of these substances. Vitamin D has historically been known to play an important role in the maintenance of organ systems. For example, vitamin D enables normal mineralization of bone and prevents hypocalccmic tetany and is needed for bone growth and bone remodeling by osteoblasts and osteoclasts, inhibits parathyroid hormone secretion from the parathyroid gland and affects the immune system by promoting phagocytosis, anti-tumor activity, and immunomodulatory functions. Vitamin D deficiency (D-deficiency) is associated with rickets in children and osteomalacia in adults, but has recently also been linked to other systemic conditions such as secondary hyperparathyroidism (Holick, 2005a; McCarty, 2005), metabolic syndrome (Peterlik and Cross, 2005), hypertension (Li et al., 2002; Wang et al., 2008), obesity (Rajakumar et al., 2008), and diabetes mellitus (Giulietti et al., 2004; Grant, 2006), and cardiovascular disease outcomes such as stroke and congestive heart failure (Michos and Melamed, 2008; Vieth and Kimball, 2006). Several recent studies also suggest that inadequate vitamin D may predispose towards Parkinson's and other neurodegenerative diseases, mood disorders (Garcion et al., 2002; Kalueff et al., 2004a), and even tuberculosis infection (Zasloff, 2006). Vitamin D deficiency has been associated with increased incidence of multiple sclerosis (MS), Sjogren's syndrome, rheumatoid arthritis, and Crohn's disease. Systemic vitamin D levels have been suggested as a possible explanation for the latitudinal gradient in MS incidence (nearly zero at the equator and increasing with greater distance from it), and correlations have been observed between circulating vitamin D status and the risk of developing MS, as well as a protective effect of vitamin D intake in both human disease and animal models. Vitamin D therapy for MS has been shown to be safe in humans and has recently been recommended for use in double blind controlled clinical trials.
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