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By Hisham A. Shembesh Academic Unit of Oral and Maxillofacial Medicine, Pathology and Surgery School of Clinical Dentistry Claremont Crescent Sheffield, S10 2TA

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By Hisham A. Shembesh Academic Unit of Oral and Maxillofacial Medicine, Pathology and Surgery School of Clinical Dentistry Claremont Crescent Sheffield, S10 2TA By Hisham A. Shembesh Academic Unit of Oral and Maxillofacial Medicine, Pathology and Surgery School of Clinical Dentistry Claremont Crescent Sheffield, S10 2TA A thesis submitted to the Faculty of Dentistry of the University of Sheffield for the degree for Doctor of Philosophy March 2018 i SUMMARY The aim of this research was to investigate the effect of novel cytokine antagonists, tumour necrosis factor-alpha antagonist (Etanercept) and interleukin-1 antagonist (Anakinra), and interleukin-10 anti-inflammatory cytokine on the inflammatory response at the site of peripheral nerve injury, in order to establish their potential contribution on nerve regeneration and determine their potential effect on the reduction or prevention of neuropathic pain. The outcome measures of functional nerve recovery were assessed using a combination of electrophysiology to determine the rate of axon regeneration, immunohistochemistry to study immune cell immunoreactivity and their related pain markers expression, and analysis of gait coordination to determine nerve function. In addition, axonal tracing was used to quantity regenerated nerve fibres following nerve conduit repair. The results showed that the peripheral application of interleukin-1 antagonist and combination treatment of interleukin-10 and tumour necrosis factor- alpha antagonist at the time of nerve repair was significantly effective in downregulating macrophage immunoreactivity at the site of nerve injury and repair. Application also decreased expression of GFAP and IBA-1 positive glial cells in the spinal cord. Results showed that interleukin-1 antagonist or tumour necrosis factor- alpha antagonist, as single therapies did not appear to significantly improve the regenerative potential of injured axons after nerve repair. However, application of a combined therapy of tumour necrosis factor-alpha antagonist and interleukin-10 greatly improved recovery, possibly due to reduced immune response and scar tissue formation. Following poly-caprolactone nerve conduit repair, axonal tracing revealed that regenerating axons took a more uniform path in the regeneration process, following treatment with tumour necrosis factor-alpha antagonist, when compared with the sterile water treatment, where many axons displayed a disorganized pattern of regeneration. However, no significant difference in nerve function recovery was observed between the two groups. The findings contained in this work provide new insights into the role of inflammatory cytokines on functional nerve recovery and the development of neuropathic pain after peripheral nerve injury. These agents demonstrate potential as therapeutic strategies for the treatment of peripheral nerve injures. ii ACKNOWLEDGEMENTS To begin with, I would like to acknowledge my sincere thankfulness to my supervisors, Dr. Simon Atkins and Dr. Emma V. Bird. I am really grateful for the support and dedicated involvement from my supervisors in every step throughout the process of preparing this thesis. I am certain that without their continued support and invaluable guidance and encouragement over the last four years, this thesis would have never been accomplished in the right time. I would also like to record my sincere gratefulness to Professor Fiona M. Boissonade for her supervision, valuable guidance and encouragement to complete this work. I truly enjoyed working in the research environment under dedicated supervision of all my supervisors. I would like to express my sincere thanks to my colleague Emad Albadawi for his collaboration in nerve conduit repair experiment. I would like also to thank Jonathan Field and Dr. Fred Claeyssens for their contribution by providing poly-caprolactone conduit which was used in nerve conduit repair experiment. I wish to express my thankfulness to Dr. Adam Harding for his kind assistance during experiments to help keep the work track. Also, it is my pleasure to acknowledge the valuable input of Dr. Milena De Felice, who contributed to my research by giving her sincere expertise in gait functional analysis using the Catwalk system. I would like to acknowledge the kind endless help of Dr. Matthew Worsley for his technical support and providing essential materials for my research experiments. I would like also to acknowledge my sincere thanks to all staff of the Academic Unit of Oral and Maxillofacial Medicine, Pathology and Surgery at the Charles Clifford dental school. I would like to thank John Wiley and Sons, Elsevier, Neurosurgical focus, Springer and Copyright Clearance Centre for permission to use figures in this thesis. I also appreciate the financial support of the Ministry of Higher Education and Scientific Research during my PhD study. I would like to express my love and thankfulness to my wife Samira Gurji who has stood by me all through my research and who encouraged me and helped me through hard times. My love and gratitude also go out to my children Adam, Amin and Zakaria, and Marya. Hisham A. Shembesh, March 2018. iii Poster presentations The effect of local administration of TNF-α antagonist (Etanercept) on nerve regeneration following Poly-caprolactone conduits repair. Emad Albadawi, Hisham Shembesh, Adam Harding, Jonathan Field, Simon Atkins, Emma Bird, Frederik Claeyssens, John Haycock and Fiona Boissonade. Poster presentation at the 3rd Annual Neuroscience R&D Technologies Conference, London, UK, September 2017 (presented by Emad Albadawi). Effect of an interleukin-1 cytokine antagonist on functional regeneration and neuropathic pain following peripheral nerve injury. Hisham Shembesh, Emma Bird, Fiona Boissonade, Simon Atkins. Poster presentation at The Challenge of Chronic Pain, Wellcome Genome Campus, Cambridge, UK, 1- 3 March 2017. Role of peripheral Interleukin-1 cytokine in peripheral nerve injury. H Shembesh, SJ Atkins, F Boissonade, E Bird. Poster presentation at The Academic Oral and Maxillofacial Surgery conference, Sheffield, UK, 19th November 2015. Peripheral targeting of Interleukin-1 cytokine signalling pathway in peripheral nerve injury. H Shembesh, EV Bird, FM Boissonade and SJ Atkins. Poster presentation at British Society of Dental Research Annual Conference, Cardiff, UK,14-16 September 2015. iv Table of Contents Tile page ............................................................................................................. …….i Summary .................................................................................................................. ii Acknowledgments .................................................................................................. iii Poster presentations .............................................................................................. iv Table of contents ..................................................................................................... v List of figures ......................................................................................................... .x List of tables ........................................................................................................ xvii Abbreviations ..................................................................................................... xviii Chapter 1: Literature review .................................................................................... 1 1.1 Introduction ..................................................................................................... 2 1.2 Biological features of of the spinal nerves, cranial nerves and the spinal cord ...................................................................................................... 4 1.2.1 The functional unit of the nervous system ............................................. 4 1.2. 2 Anatomical and physiological features of peripheral nerve fibres ..... 7 1.2.3 The spinal nerves.....................................................................................11 1.2.4 The spinal cord.........................................................................................13 1.2.5 Glial cells...................................................................................................16 1.2.6 The cranial nerves....................................................................................19 1.3 Peripheral nerve injuries .............................................................................. 23 1.3.1 Epidemiology of peripheral nerve injuries ........................................... 23 1.3.1.1 Traumatic injury to peripheral nerves- aetiology, incidence and recovery in different extremities and nerves......................................23 1.3.1.2 Traumatic injury to cranial nerves- aetiology, incidence and recovery with different nerves.............................................................25 1.3.1.3 Sequelae following different major surgical interventions- trauma, fractures, orthognathic surgery.............................................26 1.3.1.4 Sequelae following different minor surgical interventions- lower wisdom teeth removal, local anaesthesia injection injuries, implants and root canal treatment.......................................................................27 1.3.1.5 The effect of nerve injury on patient quality of life- peripheral and v cranial nerves.......................................................................................30 1.3. 2 Classification of peripheral nerve injuries .......................................... 31 1.3. 2.1 Seddon's classification system ........................................................
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