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Beneficial Effects of Caffeine Consumption on Diabetes-Induced Alterations in the Hippocampus

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Beneficial Effects of Caffeine Consumption on Diabetes-Induced Alterations in the Hippocampus BENEFICIAL EFFECTS OF CAFFEINE CONSUMPTION ON DIABETES-INDUCED ALTERATIONS IN THE HIPPOCAMPUS João Miguel das Neves Duarte Faculdade de Ciências e Tecnologia da Universidade de Coimbra Coimbra 2008 Dissertação apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra, para prestação de provas de doutoramento em Bioquímica, na especialidade de Bioquímica. O trabalho exeprimental que constitui a presente tese foi realizado em Coimbra, Departamento de Bioquímica da Faculdade de Ciências e Tecnologia da Universidade de Coimbra e no Centro de Neurociências e Biologia Celular, e em Lausanne, no Centre d'Imagerie BioMédicale. ERRATA João Miguel das Neves Duarte PhD Thesis These are the typos and errors that should be corrected in the thesis: Page Paragraph Line Reads Should be Front page 5 2 “…especialidade de “…especialidade de Bioquímica.” Bioenergética.” xiii 1 8 “…compensação osmotica…” “…compensação osmótica…” 5 1 3 “Lunetta et al,. 1994” “Lunetta et al., 1994” 5 1 5 “Gradmann et al, 1993” “Gradmann et al., 1993” 45 3 5 “…in ethanol ethanol “…in ethanol solutions…” solutions…” 122 2 9 “…crossing and reading “…crossing and rearing events… events… 126 1 9 “…(figures 4.39C).” “…(figure 4.39C).” 138 2 7 “…and that it has…” “…and it has…” 145 2 5 “…must by related…” “…must be related…” 148 1 6 “(P>0.05, n=4, Figure 4.52D)” “(P>0.05, n=4, Figure 4.53D)” 149 1 5 “…showed a increase…” “…showed an increase…” 150 Caption of 9 “…immunoreactivity ehich “…immunoreactivity, which Figure 4.55 was…” was…” Figures 4.52 to 4.55 lack reference to the amount of protein applied in the SDS-PAGE gel. It was applied 45 µg of protein in total or nerve terminal membranes for the Western blot analysis of adenosine A1 receptor, and 25 µg for synaptic proteins, GFAP and vimentin. On page 139, Figure 4.46A is: should be: None of these errors affect the conclusions of the thesis. i Table of contents Table of contents ................................................................................................................................................. i Agradecimentos/Acknowledgments ............................................................................................................ vi Abbreviation list .............................................................................................................................................viii Resumo .............................................................................................................................................................. xii Abstract ............................................................................................................................................................. xv Publication list ................................................................................................................................................ xvii 1. Introduction ................................................................................................................................................... 1 1.1. Introduction to diabetes mellitus .................................................................................................... 3 1.1.1. Overview of glycaemia regulation ................................................................................... 3 1.1.2. Diabetic encephalopathy .................................................................................................... 4 1.1.3. Glucose homeostasis and cognitive performance .......................................................... 6 1.2. Overview of brain metabolism ....................................................................................................... 8 1.2.1. Brain glucose transport ...................................................................................................... 8 1.2.2. Brain energy metabolism ................................................................................................... 9 1.2.3. Study of brain metabolism ............................................................................................... 13 1.3. Modulation systems in the brain .................................................................................................. 16 1.3.1. Purinergic signalling systems .......................................................................................... 16 1.3.1.1. Metabolism of adenosine and adenine nucleotides ........................................ 17 1.3.1.2. ATP receptors ....................................................................................................... 19 1.3.1.3. Adenosine receptors ............................................................................................ 21 1.3.2. Endocanabinoid system ................................................................................................... 24 1.3.3. Neuroprotection by modulation systems ...................................................................... 26 2. Aim ................................................................................................................................................................ 29 3. Materials and methods .............................................................................................................................. 33 3.1. Animals ............................................................................................................................................ 35 3.1.1. Experimental models of diabetes .................................................................................... 35 3.1.2. Caffeine treatment ............................................................................................................. 36 3.2. Behavioural tasks ........................................................................................................................... 36 ii 3.2.1. Open field ........................................................................................................................... 36 3.2.2. Y-maze ................................................................................................................................ 37 3.3. Biological preparations .................................................................................................................. 37 3.3.1. Nerve terminal preparations (synaptosomes) .............................................................. 37 3.3.1.1. Nerve terminals purified by 45% Percoll gradient ......................................... 38 3.3.1.2. Nerve terminals purified by discontinuous Percoll gradient ........................ 38 3.3.2. Total membrane preparation ........................................................................................... 39 3.3.3. Hippocampal slices - preparation and superfusion ..................................................... 39 3.4. Western blot analysis ..................................................................................................................... 40 3.5. Binding assay .................................................................................................................................. 42 3.6. Real-time PCR ................................................................................................................................. 43 3.7. Immunocytochemical analysis in hippocampal nerve terminals ............................................ 44 3.8. Mouse brain histochemistry ......................................................................................................... 45 3.9. ATP quantification in the cerebrospinal fluid ............................................................................ 47 3.10. ATP release from hippocampal nerve terminals ..................................................................... 47 3.11. ATP catabolism in hippocampal nerve terminals.................................................................... 48 3.12. Analysis of adenine nucleotides by HPLC ............................................................................... 48 3.13. High-resolution NMR spectroscopy .......................................................................................... 48 3.13.1. Metabolic modelling of 13 C NMR spectra .................................................................... 49 3.14. Brain neurochemistry by in vivo localised 1H NMR spectroscopy ........................................ 50 3.14.1. Animal preparation ........................................................................................................ 50 3.14.2. Localized 1H NMR spectroscopy .................................................................................. 51 3.14.3. Determination of glucose transport kinetics ............................................................... 52 3.15. Intermediary metabolism by ex vivo 13 C NMR spectroscopy ................................................. 54 3.16. Insulin quantification ................................................................................................................... 54 3.17. Caffeine quantification ................................................................................................................ 55 3.18. Reagents ......................................................................................................................................... 55 3.19. Data presentation and statistics.................................................................................................. 56 4. Results .........................................................................................................................................................
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