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Howickkp Phd2018.Pdf UCC Library and UCC researchers have made this item openly available. Please let us know how this has helped you. Thanks! Title Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives Author(s) Howick, Kenneth P. Publication date 2018 Original citation Howick, K. P. 2018. Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives. PhD Thesis, University College Cork. Type of publication Doctoral thesis Rights © 2018, Kenneth P. Howick. http://creativecommons.org/licenses/by-nc-nd/3.0/ Item downloaded http://hdl.handle.net/10468/8017 from Downloaded on 2021-10-07T02:39:18Z Ollscoil na hÉireann, Corcaigh National University of Ireland, Cork School of Pharmacy/ Department of Anatomy & Neuroscience Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives Thesis presented by Kenneth Patrick Howick, BPharm, MPharm under the supervision of Dr. Brendan Griffin Dr. Harriët Schellekens for the degree of Doctor of Philosophy December 2018 Table of Contents Table of Contents ..................................................................................................... I List of Appendices ................................................................................................ XI Glossary of Terms ................................................................................................. XI Declaration .......................................................................................................... XIII Author Contributions........................................................................................... XIII Acknowledgments .............................................................................................. XIV Publications and presentations ............................................................................. XV Thesis Summary ................................................................................................ XVII Chapter 1 19 Evolutional perspectives on energy balance ................................................ 21 1.1 Neural basis of energy homeostasis ................................................. 22 Ghrelin and the GHSR-1a in appetite and food intake regulation ............... 26 1.2 Ghrelin - Production, Cleavage and Octanoylation ......................... 27 1.3 Role of ghrelin in homeostatic and non-homeostatic feeding ......... 29 1.4 GHSR-1a – Biodistribution and Signalling ..................................... 31 1.4.1 Central Ghrelinergic Signalling .................................................. 33 1.4.2 Peripheral Ghrelinergic Signalling ............................................. 35 1.4.3 Complementary Ghrelinergic Signalling: Gastrointestinal Motility, Glucose Homeostasis and Visceral Pain..................................... 36 I The challenge of changing food intake, from in vitro to in vivo ................. 40 1.5 GHSR1a as a promiscuous target .................................................... 40 1.6 Ghrelin and Ghrelin Ligands: Pharmacokinetic Perspectives ......... 45 1.6.1 Blood Brain Barrier Penetration ................................................. 45 1.6.2 Vagus Nerve Signalling .............................................................. 46 1.7 Ghrelin administration in Human Studies ........................................ 47 1.7.1 Acyl and Desacyl- Ghrelin—Implications for Therapeutic Approaches ................................................................................. 54 1.7.2 Synthetic Ghrelin Ligands .......................................................... 56 1.7.1 Clinical Status of synthetic Ghrelin Ligands .............................. 63 Enhancing efficacy through BBB penetration. ............................................ 63 1.8 Hunger Is the Best Sauce—Targeting the Mesolimbic Reward Circuitry .......................................................................................................... 65 1.8.1 Homeostatic “Gating” of the Reward System ............................ 70 Reward system activation: the key role of dopamine .................................. 72 1.9 Microdialysis as a tool to investigate reward system activation ...... 73 1.10 Microdialysis, dopamine and ghrelin: current status ....................... 76 Disorders of appetite: Current Status and Implications for ghrelin therapy 77 1.11 Pre-cachexia and Cachexia .............................................................. 79 1.11.1 Neuronal alterations in cachexia ................................................. 80 1.12 Obesity, anorexia and binge eating disorders .................................. 83 II 1.13 Ghrelin as a pharmacological approach for disorders of appetite .... 85 From pharmaceutical to nutraceutical – opportunities for early intervention in cachexia. ........................................................................................... 87 1.14 Dairy-derived dietary bioactives ...................................................... 88 1.14.1 Oral peptide delivery – Formulation and release perspectives ... 89 Thesis objectives .......................................................................................... 93 Chapter 2 96 Abstract ........................................................................................................ 98 Introduction ................................................................................................ 100 Materials and Methods.............................................................................. 103 2.1 Materials ........................................................................................ 103 2.2 Generation of CasHyd .................................................................... 103 2.3 Ca2+ mobilization assay for peptide GHSR-1a activity.................. 104 2.4 Calcium imaging ............................................................................ 104 2.5 HPLC characterisation of CasHyd ................................................. 105 2.6 Cell culture, in vitro transfection and lentiviral transduction ........ 105 2.7 Cumulative Food intake studies ..................................................... 106 III 2.8 Pellet preparation by extrusion-spheronisation .............................. 107 2.9 Pellet film coating .......................................................................... 108 2.10 pH susceptibility tests .................................................................... 108 2.11 In vitro dissolution studies ............................................................. 108 2.12 Peptide quantification assay ........................................................... 109 2.13 Data Analysis ................................................................................. 109 Results ........................................................................................................ 110 2.14 Activity of CasHyd on ghrelin receptor overexpressing cell line. 110 2.15 Calcium imaging on ghrelin receptor overexpressing cell line ..... 112 2.16 HPLC characterization of CasHyd ................................................. 114 2.17 GHSR-1a activation by CasHyd in neuronal cells in vitro. ........... 115 2.18 Additive and synergistic effects of the novel dairy-derived hydrolysate on ghrelin-mediated GHSR-1a activation. ..................................... 117 2.19 Cumulative food intake studies after intraperitoneal injection of peptide solution ........................................................................................... 120 2.20 Cumulative Food Intake studies after oral administration of peptide solution ........................................................................................... 121 IV 2.21 pH susceptibility of CasHyd .......................................................... 122 2.22 Delivery system (pellet) characterization work ............................. 123 2.23 GHSR-1a activity of peptide post-encapsulation ........................... 124 2.24 Cumulative food intake studies after oral administration of peptide encapsulated in gastro-protective pellets ....................................... 125 Discussion .................................................................................................. 127 Conclusion ................................................................................................. 132 Supplementary materials............................................................................ 133 2.25 Blood biomarker analysis .............................................................. 133 Chapter 3 135 Abstract ...................................................................................................... 137 Introduction ................................................................................................ 138 Materials and Methods............................................................................... 142 3.1 Materials ........................................................................................ 142 3.2 Generation of FHI-2571 ................................................................. 142 3.3 Ca2+ mobilization assay for peptide ghrelin receptor activity pre- and post-encapsulation .......................................................................... 143 V 3.4 Pellet preparation by extrusion-spheronisation .............................. 143 3.5 Pellet film coating .......................................................................... 144 3.6 pH susceptibility tests ...................................................................
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