PTS1 Regulation of Brain Met Enk Levels in Alcoholism

Summary

Principal Investigator: William Banks
Affiliation: Saint Louis University
Country: USA
Abstract: Addiction to ethanol is a significant problem in our society and is a leading cause of morbidity and mortality in the population. Major changes in neurochemistry, such as in the brain levels of the opiate peptide methionine enkephalin Met-En k , have been associated with exposure to ethanol. It is our long term goal to elucidate the mechanisms and significance of these changes in Met-Enk and to design therapeutic interventions directed at their reversal. The level of Met-Enk in the brain has been linked to ethanol ingestion and withdrawal seizures while treatment with enkephalins, their analogs, or blockers of their enzymatic degradation can decrease ethanol drinking and prevent ethanol withdrawal seizures. The level of Met-Enk in the brain is determined by a balance of synthesis, release, degradation, and transport across the blood-brain barrier BB by PTS-1, which carries Met-Enk from the brain to the blood. Our work has confirmed that PTS-1 is a major regulator of the level of Met-Enk in the brain of ethanol-naive mice and that during physical dependence to and withdrawal from ethanol the control of the level of Met-Enk in the brain is post-translational and mediated at least partially by PTS-1. In the requested funding period, we will determine the relative importance during physical dependence to and withdrawal from ethanol of PTS-1 to that of other post-translational mechanisms that affect Met-Enk levels in the brain.
Funding Period: 2001-06-01 - 2006-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier
    Naoko Nonaka
    Department of Oral Anatomy, Showa University School of Dentistry, Tokyo, Japan
    Exp Neurol 191:137-44. 2005
  2. ncbi Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models
    Dilek Dogrukol-Ak
    Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey
    J Cereb Blood Flow Metab 29:411-22. 2009
  3. ncbi Loss of appendicular muscle mass and loss of muscle strength in young postmenopausal women
    Yves M Rolland
    Geriatric Research, Education and Clinical Center, St Louis VA Medical Center, St Louis, MO 63104, USA
    J Gerontol A Biol Sci Med Sci 62:330-5. 2007
  4. ncbi Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, WAB, 915 N Grand Blvd, St Louis, MO 63106, USA
    Brain Res 1116:215-21. 2006
  5. ncbi Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM)
    A L Petursdottir
    Department of Physiology, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, IS 101 Reykjavik, Iceland
    Neurobiol Aging 28:1170-8. 2007
  6. ncbi Effects of chronic ethanol administration on brain interstitial fluid levels of Methionine-enkephalin as measured by microdialysis in vivo
    Akihiko Urayama
    Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine and GRECC, Veterans Affairs Medical Center in St. Louis, 915N Grand Blvd, St. Louis, MO 63106, USA
    Peptides 27:2201-6. 2006
  7. ncbi Ghrelin controls hippocampal spine synapse density and memory performance
    Sabrina Diano
    Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Nat Neurosci 9:381-8. 2006
  8. ncbi Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells
    Joachim Spranger
    Dept of Clinical Nutrition, German Institute of Human Nutrition Potsdam, Arthur Scheunert Allee 114 116, 14558 Nuthetal, Germany
    Diabetes 55:141-7. 2006
  9. ncbi Preproenkephalin targeted antisenses cross the blood-brain barrier to reduce brain methionine enkephalin levels and increase voluntary ethanol drinking
    William A Banks
    Veterans Affairs Medical Center and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, 915N Grand Blvd, St Louis, MO 63106, USA
    Peptides 27:784-96. 2006
  10. ncbi Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumors
    Laura B Jaeger
    Department of Pharmacological and Physiological Sciences, Division of Geriatrics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
    Proc Natl Acad Sci U S A 102:12495-500. 2005

Scientific Experts

  • William Banks
  • Joachim Spranger
  • Yves M Rolland
  • A L Petursdottir
  • Naoko Nonaka
  • Ryota Nakaoke
  • Susan A Farr
  • Laura B Jaeger
  • Dilek Dogrukol-Ak
  • John E Morley
  • Michael L Niehoff
  • Jan S Ryerse
  • Akihiko Urayama
  • Sabrina Diano
  • Elena V Batrakova
  • Tomoya Nakamachi
  • Hirokazu Ohtaki
  • Seiji Shioda
  • Vijaya B Kumar
  • John C Edwards
  • Sulekha Verma
  • Ivaldo da Silva
  • Stephen C Benoit
  • Lin Xu
  • F Spencer Gaskin
  • Shirly Pinto
  • Matthias H Tschop
  • Frederich S Gaskin
  • Kelvin A Yamada
  • Mark W Sleeman
  • Ewan C McNay
  • Balazs Horvath
  • Kevin King
  • Robert S Sherwin
  • Tamas L Horvath
  • Jozsef L Varga
  • Serguei V Vinogradov
  • Alexander V Kabanov
  • Sandra M Robinson
  • Seji Shioda
  • Andrew V Schally
  • Masami Niwa

Detail Information

Publications15

  1. ncbi Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier
    Naoko Nonaka
    Department of Oral Anatomy, Showa University School of Dentistry, Tokyo, Japan
    Exp Neurol 191:137-44. 2005
    ..LPS did not alter the efflux of I-PACAP from the CNS. In conclusion, PTS-6 remains active and should be able to deliver therapeutic amounts of PACAP to the CNS in brain injuries involving cytokine release and BBB disruption...
  2. ncbi Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models
    Dilek Dogrukol-Ak
    Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey
    J Cereb Blood Flow Metab 29:411-22. 2009
    ..This represents the first isolation from BBB tissue of a peptide transporter and shows that inhibition of peptide efflux pumps is a potential strategy for drug delivery to brain...
  3. ncbi Loss of appendicular muscle mass and loss of muscle strength in young postmenopausal women
    Yves M Rolland
    Geriatric Research, Education and Clinical Center, St Louis VA Medical Center, St Louis, MO 63104, USA
    J Gerontol A Biol Sci Med Sci 62:330-5. 2007
    ..1 +/- 4.3 years) in a 24-36-month prospective study...
  4. ncbi Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier
    William A Banks
    GRECC, Veterans Affairs Medical Center St Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, WAB, 915 N Grand Blvd, St Louis, MO 63106, USA
    Brain Res 1116:215-21. 2006
    ..Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42...
  5. ncbi Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM)
    A L Petursdottir
    Department of Physiology, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, IS 101 Reykjavik, Iceland
    Neurobiol Aging 28:1170-8. 2007
    ..The oldest age group contained the highest concentration of alpha-tocopherol, indicating a protection against oxidative damage of PUFA in brain membrane phospholipids...
  6. ncbi Effects of chronic ethanol administration on brain interstitial fluid levels of Methionine-enkephalin as measured by microdialysis in vivo
    Akihiko Urayama
    Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine and GRECC, Veterans Affairs Medical Center in St. Louis, 915N Grand Blvd, St. Louis, MO 63106, USA
    Peptides 27:2201-6. 2006
    ..5% of control levels. This decrease was restored to the level of control by withdrawing ethanol. These reversible changes in ISF and serum are readily explained by the known changes in the efflux activity of PTS-1 at the BBB...
  7. ncbi Ghrelin controls hippocampal spine synapse density and memory performance
    Sabrina Diano
    Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Nat Neurosci 9:381-8. 2006
    ..Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes...
  8. ncbi Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells
    Joachim Spranger
    Dept of Clinical Nutrition, German Institute of Human Nutrition Potsdam, Arthur Scheunert Allee 114 116, 14558 Nuthetal, Germany
    Diabetes 55:141-7. 2006
    ....
  9. ncbi Preproenkephalin targeted antisenses cross the blood-brain barrier to reduce brain methionine enkephalin levels and increase voluntary ethanol drinking
    William A Banks
    Veterans Affairs Medical Center and Division of Geriatrics, Department of Internal Medicine, Saint Louis University School of Medicine, 915N Grand Blvd, St Louis, MO 63106, USA
    Peptides 27:784-96. 2006
    ..Taken together, these results used pharmacokinetic, immunochemical, and behavioral methods to show that PS-ODN antisenses that readily cross the BBB can decrease brain levels of Met-Enk and increase voluntary ethanol drinking...
  10. ncbi Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumors
    Laura B Jaeger
    Department of Pharmacological and Physiological Sciences, Division of Geriatrics, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
    Proc Natl Acad Sci U S A 102:12495-500. 2005
    ..v.-administered 131I-JV-1-42 readily crosses the blood-brain barrier and accumulates in the brain. This finding indicates that GHRH antagonists could provide a potential treatment for malignant glioblastomas...
  11. ncbi Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery
    Elena V Batrakova
    Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198, USA
    Bioconjug Chem 16:793-802. 2005
    ..These results show that point modification can improve delivery of even highly impermeable polypeptides to the brain...
  12. ncbi In vitro methods in the study of viral and prion permeability across the blood-brain barrier
    Ryota Nakaoke
    Department of Pharmacology 1, Nagasaki University School of Medicine, Nagasaki, Japan
    Cell Mol Neurobiol 25:171-80. 2005
    ..Our laboratories have used in vitro methods to study these agents. (3) Here, we review some of the results form our laboratories and those of others...
  13. ncbi Human immunodeficiency virus type 1 transport across the in vitro mouse brain endothelial cell monolayer
    Ryota Nakaoke
    Geriatric Research, Educational, and Clinical Center, Veterans Affairs Medical Center, St. Louis, MO 63106, USA
    Exp Neurol 193:101-9. 2005
    ..HIV-1 taken up from luminal side by monolayers of brain endothelial cells was mainly released to the luminal side. HIV-1 efflux mechanisms are different from influx mechanisms...
  14. ncbi Effects of a behaviorally active antibody on the brain uptake and clearance of amyloid beta proteins
    William A Banks
    GRECC, Veterans Affairs Medical Center, 915 N Grand Blvd, St Louis, MO 63106, USA
    Peptides 26:287-94. 2005
    ....
  15. ncbi Effect of dietary n-3 polyunsaturated fatty acids on brain lipid fatty acid composition, learning ability, and memory of senescence-accelerated mouse
    Anna L Petursdottir
    Department of Physiology, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, IS 101, Reykjavik, Iceland
    J Gerontol A Biol Sci Med Sci 63:1153-60. 2008
    ..This study demonstrates that, in mature animals, DHA is incorporated into brain phospholipids and that dietary n-3 PUFA is associated with delay in cognitive decline...