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The Neuroprotective and Behavioural Effects of Group III Metabotropic Glutamate Receptor Ligands in Rodent Models of Parkinson’S Disease

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The Neuroprotective and Behavioural Effects of Group III Metabotropic Glutamate Receptor Ligands in Rodent Models of Parkinson’S Disease The Neuroprotective and Behavioural Effects of Group III Metabotropic Glutamate Receptor Ligands in Rodent Models of Parkinson’s Disease Claire J. Williams July 2015 A thesis submitted for the degree of Doctor of Philosophy of Imperial College London Wolfson Neuroscience Laboratories Division of Brain Sciences Imperial College Faculty of Medicine Hammersmith Hospital Campus Burlington Danes Building Du Cane Road London W12 0NN 1 Declaration of originality I declare that this thesis is my own work and has not been submitted in any form for another qualification at any university or other institution of tertiary education. Information derived from published or unpublished work of others has been acknowledged in this thesis and a list of references is included. Claire J. Williams 20/07/2015 Copyright declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or distribution, researchers must make clear to others the license terms of this work. 2 Acknowledgements I would firstly like to express my thanks to my supervisor Professor David Dexter for his much appreciated support, patience, guidance and encouragement during this PhD, all of which have helped me to develop as a scientist. Special thanks go to Dr Ian Harrison, my 'work husband', for his resolute friendship, enthusiastic teaching, invaluable help and sympathetic ear. You have been a huge support and a core part of my experience at Imperial College. Also to my good friends from across the office and lab, Eleanor and Renée, thank you for your unending moral support, for making me laugh regularly and for supplying me with baked goods at any time of the day or night to keep me on track. Particular thanks go to both past and present Dexter lab members, I'm so grateful for all of your knowledgeable input and great company in and out of the lab. I am incredibly grateful to those who share my enthusiasm for public engagement and provided an opportunity to get involved in exciting ventures like the Pint of Science Festival and Meet the Scientist events- Michael, Praveen, Christina, Lucy, Amy and many others, your enthusiasm and drive was infectious and inspiring, thank you. Also to the wonderful cake club members who brought joy and cake into my life, thank you for making Mondays the best day of the week. To my Imperial colleagues and friends in and outside of the department, thank you for the random chats and for making my experience at Imperial special and memorable. I am indebted to the CBS staff that provided dedicated and brilliant animal care and advice during my time at Imperial. I am also hugely grateful to Parkinson's UK for funding my PhD and for providing much encouragement, support and motivation during your group visits. To all of my friends outside of the lab, thank you for being there and for pushing me on, no matter how much I moaned! I cannot express how grateful I am to my family, who have tirelessly supported me through all the ups and downs of the last few years and endured my determined need to challenge myself; I owe you so much. Huge thanks also go to the Charalambou family for their generosity and support at all times. Lastly, I want to thank my wonderful partner Ciarán, your love, patience, support and encouragement have been unwavering throughout, and I couldn't have got here without you. 3 Abstract Current therapies for Parkinson's disease are able to ameliorate the symptoms in the early stages, however as the disease progresses, they become less effective and patients often develop debilitating side effects. There is currently a significant unmet need for disease modifying or neuroprotective drugs to slow the rate of disease progression and provide long-term symptomatic relief. Novel therapeutics that can provide symptomatic relief whilst attenuating the ongoing neurodegeneration are therefore sought. The targeting of metabotropic glutamate (mGlu) receptors has become a therapeutic focus in recent years. The group III mGlu receptors are the focus of this thesis as they currently hold the most therapeutic promise, with evidence suggesting activation of these receptors not only modulates aberrant neurotransmission in the basal ganglia to provide symptom relief, but also provides neuroprotective effects in the nigrostriatal system through a variety of mechanisms. Recent advances in the development of subtype-selective ligands that cross the blood-brain barrier provides the ability to explore the variety of functions associated with targeting individual group III mGlu receptor subtypes in a clinically relevant manner. In order to determine the potential of these receptors as suitable targets for novel therapies, the antiparkinsonian activity and neuroprotective effects of group III mGlu receptor subtypes were investigated using two novel selective ligands in the lactacystin model, which features altered protein accumulation, progressive neuronal death and development of motor deficits. Neither ligand reduced motor symptoms effectively, and no robust neuroprotection was detected. Potential anti-inflammatory mechanisms of one compound were then investigated in vivo and in vitro but showed no clear effect. Selectively targeting group III mGlu receptors did not hold the neuroprotective or antiparkinsonian potential that was initially predicted. Collectively, these studies demonstrate the importance of testing therapies in a variety of models demonstrating different aspects of disease pathogenesis. 4 Table of contents Declaration of originality .............................................................................................................. 2 Copyright declaration ................................................................................................................... 2 Acknowledgements...................................................................................................................... 3 Abstract ....................................................................................................................................... 4 Table of contents ......................................................................................................................... 5 List of figures ............................................................................................................................. 10 List of tables .............................................................................................................................. 14 Abbreviations ............................................................................................................................ 15 Publications ............................................................................................................................... 17 Chapter 1: Introduction .............................................................................................................. 18 1.1 Parkinson’s Disease ............................................................................................................... 19 1.1.1 Overview ..................................................................................................................... 19 1.1.2 Epidemiology of Parkinson's disease .......................................................................... 19 1.1.3 Genetic and idiopathic causes .................................................................................... 20 1.1.4 Clinical manifestations ............................................................................................... 21 1.1.4.1 Motor symptoms ............................................................................................. 22 1.1.4.2 Non-motor features ........................................................................................ 22 1.1.4.3 Clinical diagnosis of Parkinson's disease ......................................................... 24 1.1.5 Neuropathological features ........................................................................................ 24 1.1.5.1 Neuropathological staging .............................................................................. 26 1.1.6 The Basal Ganglia: Pathophysiology of Parkinson's disease ...................................... 26 1.2 Pathogenic mechanisms ........................................................................................................ 30 1.2.1 Mitochondrial dysfunction and oxidative stress ........................................................ 30 1.2.2 Glutamate dysregulation and excitotoxicity .............................................................. 31 1.2.3 Proteasome dysfunction ............................................................................................ 34 1.2.4 Inflammation .............................................................................................................. 36 1.3 Modelling Parkinson's disease in animals ............................................................................. 37 1.3.1 Genetic models ........................................................................................................... 38 1.3.2 Toxin models .............................................................................................................. 39 1.4 Current therapies
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