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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 17 September 2009 (17.09.2009) WO 2009/114533 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/52 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, PCT/US2009/036671 EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 10 March 2009 (10.03.2009) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (25) Filing Language: English NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (26) Publication Language: English SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/035,250 10 March 2008 (10.03.2008) US (84) Designated States (unless otherwise indicated, for every 61/037,145 17 March 2008 (17.03.2008) 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): COR¬ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, NELL UNIVERSITY [US/US]; Cornell Center for TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Technology, Enterprise & Commercialization, 395 Pine ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Tree Road, Suite 310, Ithaca, NY 14850 (US). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (72) Inventor; and MR, NE, SN, TD, TG). (75) Inventor/Applicant (for US only): BYNOE, Margaret, S. [US/US]; 101 Park Lane, Ithaca, NY 14850 (US). Published: (74) Agents: GOLDMAN, Michael, L. et al; Nixon Peabody — without international search report and to be republished LLP, Patent Group, 1100 Clinton Square, Rochester, NY upon receipt of that report (Rule 48.2(gf) 14 604-1792 (US). (54) Title: MODULATION OF BLOOD BRAIN BARRIER PERMEABILITY (57) Abstract: The present invention relates to a method of increasing blood brain barrier permeability in a subject. This method involves selecting a subject who would benefit from increased blood brain barrier permeability and subjecting the selected subject to a treatment. That treatment increases adenosine level and/or bioavailability, modulates adenosine receptors, and/or increases CD73 level and/or activity under conditions effective to increase blood brain barrier permeability in the subject. Methods of de- creasing blood brain barrier permeability in a subject, treatment of a subject for a disorder or condition of the central nervous sys - tern, and screening compounds effective in increasing blood brain barrier permeability, as well as pharmaceutical agents are also disclosed. MODULATION OF BLOOD BRAIN BARRIER PERMEABILITY [0001] This application claims the benefit of U S Provisional Patent Application Serial Nos 61/035,250, filed March 10, 2008, and 61/037,145, filed March 17, 2008, which are hereby incorporated by reference in their entirety FIELD OF THE INVENTION [0002] The present invention relates to modulation of blood bram barrier permeability BACKGROUND OF THE INVENTION [0003] The barriers to blood entering the central nervous system ("CNS") are herein collectively referred to as the blood bram barrier ("BBB") The BBB is a tremendously tight-knit layer of endothelial cells that coats 400 miles of capillaries and blood vessels in the bram (Ransohoff et al , "Three or More Routes for Leukocyte Migration Into the Central Nervous System," Nature Rev Immun 3 569-581 (2003)) The nearly impermeable junctions between BBB cells are formed by the mterdigitation of about 20 different types of proteins Molecules must enter a BBB cell through membrane-embedded protein transporters or by slipping directly through its waxy outer membrane Once mside, foreign compounds must avoid a high concentration of metabolic enzymes and a variety of promiscuous protein pumps primed to eliminate foreign substances Having avoided these obstacles, foreign molecules must then pass through the inner membrane of a BBB cell to finally reach the bram These elaborate defenses allow the BBB to sequester the bram from potential harm, but the BBB also obstructs delivery of neurological drugs to a site of disease in the bram Researchers in academia and the biotech and pharmaceutical industries are learning to bypass the BBB or allow it to let potential drugs into the bram They are designing small drugs that can passively diffuse through the BBB or travel on nutrient transporters to get inside the bram Others are attaching potential therapeutics designed so that the bram will unwittingly engulf them [0004] The capillaries that supply blood to the tissues of the bram constitute the blood bram barrier (Goldstein et al , "The Blood-Bram Barrier," Scientific American 255 74-83(1986), Pardπdge, "Receptor-Mediated Peptide Transport Through the Blood-Bram Barrier," Endocrin Rev 7 314-330(1986)) The endothelial cells which form the bram capillaries are different from those found in other tissues in the body Bram capillary endothelial cells are joined together by tight intercellular junctions which form a continuous wall against the passive diffusion of molecules from the blood to the bram and other parts of the CNS These cells are also different in that they have few pmocytic vesicles which in other tissues allow somewhat unselective transport across the capillary wall Also lacking are continuous gaps or channels running between the cells which would allow unrestricted passage [0005] The blood-bram barrier functions to ensure that the environment of the bram is constantly controlled The levels of various substances in the blood, such as hormones, ammo acids, and ions, undergo frequent small fluctuations which can be brought about by activities such as eating and exercise (Goldstein et al , "The Blood-Bram Barrier," Scientific American 255 74-83(1986), Pardπdge, "Receptor-Mediated Peptide Transport Through the Blood-Bram Barrier," Endocrin Rev 7 314-330(1986)) If the bram was not protected by the blood bram barrier from these variations in serum composition, the result could be uncontrolled neural activity [0006] The isolation of the bram from the bloodstream is not complete If this were the case, the bram would be unable to function properly due to a lack of nutrients and because of the need to exchange chemicals with the rest of the body The presence of specific transport systems within the capillary endothelial cells assures that the bram receives, in a controlled manner, all of the compounds required for normal growth and function In many instances, these transport systems consist of membrane-associated proteins, which selectively bind and transport certain molecules across the barrier membranes These transporter proteins are known as solute carrier transporters [0007] Although it is believed that the BBB serves a protective function under normal conditions by protecting the CNS from exposure to potentially toxic compounds, in CNS disease, the BBB may thwart therapeutic efforts by hindering the entry of therapeutic compounds into the CNS For example, although many bacterial and fungal infections may be readily treated where the site of the infection is outside the CNS, such infections in the CNS are often very dangerous and very difficult to treat due to the inability to deliver effective doses of drugs to the site of the infection Similarly, the action of the BBB makes treatment of cancer of the bram more difficult than treatment of cancers located outside the CNS Even where it may be possible to deliver an effective dose of drug into the CNS by administering very large amounts of drug outside of the CNS, the drug levels outside the CNS (such as in the blood) are then often so high as to reach toxic levels deleterious to the kidneys, liver, and other vital organs Accordingly, there is need in the art for methods to improve the delivery of compounds into the CNS [0008] In addition, patients suffering from edema, bram traumas, stroke and multiple sclerosis exhibit a breakdown of the BBB near the site of primary insults The level of breakdown can have profound effects on the clinical outcome of these diseases For instance, the degree of BBB breakdown in patients suffering from multiple sclerosis ("MS") is correlated to the severity of the disease It has been shown using Magnetic Resonance Imaging ("MRI") that, when a person is undergoing an MS "attack," the blood-bram barrier has broken down in a section of the bram or spinal cord, allowing white blood cells called T lymphocytes to cross over and destroy the myelin [0009] Despite the importance of this barrier, very little is known about the molecular mechanisms controlling the integrity and/or permeability of the BBB Thus, there remains a considerable need for compositions and methods that facilitate such research and especially for diagnostic and/or therapeutic applications [0010] The present invention is directed to overcoming these and other deficiencies in the art SUMMARY OF THE INVENTION [0011] The present invention relates to a method of increasing blood bram barrier permeability in a subject This method involves selecting a subject who would benefit from increased blood bram barrier permeability and subjecting the
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  • The Effects of Adenosine Antagonists on Distinct Aspects of Motivated Behavior: Interaction with Ethanol and Dopamine Depletion

    The Effects of Adenosine Antagonists on Distinct Aspects of Motivated Behavior: Interaction with Ethanol and Dopamine Depletion

    Facultat de Ciències de la Salut Departament de Psicologia Bàsica, Clínica i Psicobiologia The effects of adenosine antagonists on distinct aspects of motivated behavior: interaction with ethanol and dopamine depletion. PhD Candidate Laura López Cruz Advisor Dr. Mercè Correa Sanz Co-advisor Dr. John D.Salamone Castelló, May 2016 Als meus pares i germà A Carlos AKNOWLEDGEMENTS This work was funded by two competitive grants awarded to Mercè Correa and John D. Salamone: Chapters 1-4: The experiments in the first chapters were supported by Plan Nacional de Drogas. Ministerio de Sanidad y Consumo. Spain. Project: “Impacto de la dosis de cafeína en las bebidas energéticas sobre las conductas implicadas en el abuso y la adicción al alcohol: interacción de los sistemas de neuromodulación adenosinérgicos y dopaminérgicos”. (2010I024). Chapters 5 and 6: The last 2 chapters contain experiments financed by Fundació Bancaixa-Universitat Jaume I. Spain. Project: “Efecto del ejercicio físico y el consumo de xantinas sobre la realización del esfuerzo en las conductas motivadas: Modulación del sistema mesolímbico dopaminérgico y su regulación por adenosina”. (P1.1B2010-43). Laura López Cruz was awarded a 4-year predoctoral scholarship “Fornación de Profesorado Universitario-FPU” (AP2010-3793) from the Spanish Ministry of Education, Culture and Sport. (2012/2016). TABLE OF CONTENTS ABSTRACT ...................................................................................................................1 RESUMEN .....................................................................................................................3