Genomes and Genes
PTS1 Regulation of Brain Met Enk Levels in Alcoholism
Principal Investigator: William Banks
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
- Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscleM T Haren
Geriatric Research, Education and Clinical Center GRECC, St Louis Veterans Affairs Medical Center, St Louis, MO 63125, USA
Int J Androl 34:55-68. 2011..These findings identify specific mechanisms by which testosterone may regulate skeletal muscle glucose and protein metabolism...
- Effect of dietary n-3 polyunsaturated fatty acids on brain lipid fatty acid composition, learning ability, and memory of senescence-accelerated mouseAnna 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...
- Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke modelsDilek 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...
- Loss of appendicular muscle mass and loss of muscle strength in young postmenopausal womenYves 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...
- Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrierWilliam 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...
- 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...
- Effects of chronic ethanol administration on brain interstitial fluid levels of Methionine-enkephalin as measured by microdialysis in vivoAkihiko 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...
- Ghrelin controls hippocampal spine synapse density and memory performanceSabrina 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...
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Dept of Clinical Nutrition, German Institute of Human Nutrition Potsdam, Arthur Scheunert Allee 114 116, 14558 Nuthetal, Germany
Diabetes 55:141-7. 2006....
- Preproenkephalin targeted antisenses cross the blood-brain barrier to reduce brain methionine enkephalin levels and increase voluntary ethanol drinkingWilliam 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...
- Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumorsLaura 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...
- Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain deliveryElena 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...
- In vitro methods in the study of viral and prion permeability across the blood-brain barrierRyota 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...
- Human immunodeficiency virus type 1 transport across the in vitro mouse brain endothelial cell monolayerRyota 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...
- Effects of a behaviorally active antibody on the brain uptake and clearance of amyloid beta proteinsWilliam A Banks
GRECC, Veterans Affairs Medical Center, 915 N Grand Blvd, St Louis, MO 63106, USA
Peptides 26:287-94. 2005....
- Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrierNaoko 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...