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Regulation of Extracellular Arginine Levels in the Hippocampus in Vivo

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Regulation of Extracellular Arginine Levels in the Hippocampus in Vivo Regulation of Extracellular Arginine Levels in the Hippocampus In Vivo by Joanne Watts B.Sc. (Hons) r Thesis submitted for the degree of Doctor of Philosophy in the Faculty of Science, University of London The School of Pharmacy University of London ProQuest Number: 10105113 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10105113 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Nitric oxide (NO) has emerged as an ubiquitous signaling molecule in the central nervous system (CNS). NO is synthesised from molecular oxygen and the amino acid L-arginine (L- ARG) by the enzyme NO synthase (NOS), and the availability of L-ARG has been implicated as the limiting factor for NOS activity. Previous studies have indicated that L- ARG is localised in astrocytes in vitro and that the in vitro activation of non-N-methyl-D- aspartate (NMDA) receptors, as well as the presence of peroxynitrite (ONOO ), led to the release of L-ARG. Microdialysis was therefore used in this study to investigate whether this held true in vivo. The results indicated that, while L-ARG was localised in glia in vivo and the infusion of a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) caused the release of L-ARG, this increase in extracellular L-ARG levels did not drive the NOS reaction. The increased L-ARG levels were halved by the coinfusion of CNQX but not totally inhibited. NMDA receptor activation is recognised as a major pathway of NOS activation and hence NO production and, while the results of this study concur, the results herein also suggest no need for increased L-ARG in the extracellular space as a prerequisite for NOS activation. Interesting results were also achieved using the NOS inhibitors N“- nitro-L-ARG methyl ester (L-NAME) and 7-nitroindazole (7-NI). Both inhibitors increased the basal activity of NOS and production of NO, while each drug had contrasting effects on the NMDA-stimulated response. L-NAME blocked the increased NOS activity with no effect on NO production while 7-NI had no effect on NOS but blocked the production of NO. In conclusion, the regulation of the supply of L-ARG for NOS in vivo is far more complicated than in vitro studies suggest. 11 A cknowledf^ements Acknowledgements There are a great number of people without whom none of this would have been possible. Many thanks go to Professor Trevor Smart and Professor Alex Thomson for allowing me to use the facilities at the School. I would like to express my gratitude to my supervisors Drs Brian Pearce and Peter Whitton for their help and advice, with special thanks to Brian for reading this thesis. Thanks also to the Medical Research Council and the School of Pharmacy for financial support. I am extremely grateful for the help and advice imparted by Dr Les Fowler, especially for his considerable expertise regarding HPLC. Thanks also to Analytix for the loan of the NOA Many thanks also to Steve Coppard, Dave Zeraschi and Donna Howell for all their assistance with the volunteers. I would also like to thank several people in the School who have supported me throughout and kept me amused. These include Vicky Welsh, Kshipra Desai, Jonathan Wilkinson, Raj Tiwary, Nicola Wilson and Chris Courtice. Thanks must also go to the staff of the computer and multimedia units for their support, especially Annie Cavanagh, Graham Florence and Paul Cuthbert. Ill Dedication !for 9drs 9{.Cv[. !Parton IV Table o f Contents Table of Contents Page Chapter 1: General Introduction ............................................................................................. 20 1.1 History of Nitric Oxide ........................................................................................ 21 1.2 Synthesis of NO .................................................................................................... 22 1.3 Amino acid transporters ........................................................................................ 27 1.4 NOS isoenzymes .................................................................................................... 29 1.4.1 Structure and fu n ctio n ........................................................................... 29 1.4.2 Calcium and calmodulin regulation ................................................. 31 1.4.3 Expressional regulation ........................................................................ 32 1.4.4 Enzyme activation and cellular localisation ................................... 33 1.4.5 The arginine paradox and eN O S ........................................................ 39 1.4.6 The roles of haem and tetrahydrobiopterin (BH 4 ) .......................... 40 1.5 NO and signal transduction ................................................................................. 41 1.6 NOS in h ib ito rs ........................................................................................................ 44 1.6.1 Mechanisms of in h ib itio n ................................................................... 44 1.6.2 The oxygenase dom ain ........................................................................ 44 1.6.3 The calmodulin binding s ite ............................................................... 48 1.6.4 The reductase dom ain .......................................................................... 49 1.6.5 Arginine transporters ............................................................................. 49 1.6.6 Inhibitor specificity ............................................................................... 50 1.7 NO releasing com pounds ...................................................................................... 53 1.7.1 General properties of NO donors ...................................................... 53 1.7.2 Direct donors ........................................................................................... 53 1.7.3 Donors requiring metabolism ............................................................. 57 1.7.4 Bifunctional donors ............................................................................... 58 1.8 Roles of NO throughout the body ...................................................................... 58 1.8.1 The cardiovascular system ................................................................. 58 1.8.2 Host defence ........................................................................................... 60 1.8.3 The peripheral nervous system .......................................................... 63 1.9 NO in the central nervous system ...................................................................... 64 1.9.1 Glutamatergic NO release................................................................. 64 V Table o f Contents 1.9.2 Glutamate as a neurotransmitter ........................................................ 65 1.9.3 The NMDA receptor ............................................................................. 67 1.9.3.1 Special features of the NMDA receptor .......................... 67 1.9.3.2 Molecular biology of the NMDA receptor ..................... 70 1.9.4 The AMPA receptor ............................................................................. 71 1.9.5 NO in neurotransmission .................................................................... 73 1.10 A im s ...................................................................................................................... 78 Chapter 2: Materials and M ethods ........................................................................................ 79 2 . 1 /« v/vo microdialysis ............................................................................................. 80 2.1.1 Probe Construction ............................................................................... 80 2.1.2 In vitro recoveries of amino acids ...................................................... 82 2.1.3 Stereotaxic implantation ...................................................................... 84 2.1.4 Validity of microdialysis...................................................................... 8 8 2.1.5 Microdialysis........................................................................................... 90 2.1 . 6 Anatomical verification of probe placement ................................... 90 2.2 Analysis of amino acids ........................................................................................ 92 2.2.1 Detection of amino acids ................................................................. 92 2.2.2 Derivatisation of amino acids ............................................................. 92 2.3 High performance liquid chromatography (H PLC) ........................................ 93 2.3.1 HPLC Apparatus .................................................................................... 93 2.3.2 Analysis.................................................................................................... 95 2.3.3 Mobile phase composition ................................................................. 95 2.3.4 Identification
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