• Abstract and Figures
• Public Full-text

THE UNIVERSITY OF NEW SOUTH WALES Translational Neuroscience Facility School of Medical Sciences Faculty of Medicine UNSW Australia A thesis in fulfilment of the requirements for the degree of: Masters Investigating Neuroprotectants for the Treatment of Chemotherapy-Induced Peripheral Neuropathy by Munawwar Abdulla Supervisor: Dr. Gila Moalem-Taylor Co-supervisor: Dr. Justin Lees Co-supervisor: Dr. Patsie Pollie August, 2018 i The University of New South Wales Thesis/Dissertation Sheet Surname or Family name: Abdulla First name/s: Munawwar Abbreviation for degree as given in the University calendar: MSc School: School of Medical Sciences Faculty: Medicine Title: Investigating neuroprotectants for the treatment of chemotherapy-induced peripheral neuropathy Abstract 350 words maximum: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of many chemotherapy regimens and is becoming a more prevalent issue as the longevity of cancer patients continues to increase. Sensory symptoms include neuropathic pain, paraesthesia, and numbness and usually spread in a glove-and-stocking distribution. At present, there are no effective medications to treat or prevent CIPN, and the mechanisms by which symptoms are induced have not been fully elucidated. Paclitaxel (PTX) is a commonly used chemotherapeutic that induces neuropathy in a high percentage of patients. The broad aim of this thesis was to establish a model of CIPN in vitro and in vivo and test clinically approved drugs for potential neuroprotective effects. Since the dorsal root ganglion (DRG) has been implicated in CIPN, we cultured dissociated primary DRG neurons from 5-week-old C57BL/6 mice and treated them with PTX to observe neurotoxic effects. We found a marked reduction of neurite outgrowth per neuron and significant morphological changes. Next, we tested several drugs selected from the literature (ibudilast, nicotinamide mononucleotide, resatorvid, amiloride, duloxetine, safinamide) for their potential neuroprotective effects in this model and of those, found that amiloride moderately but significantly prevented the reduction of neurite outgrowth at a certain concentration, although could be harmful if the concentration was too high. We then established a chronic CIPN model in C57BL/6 mice using 6 injections of PTX over a two-week period. PTX-treated mice developed mechanical allodynia, an increase in acetylated tubulin representing damage in the sciatic nerve, increased macrophage presence in the DRG and increased glial cell activation in the spinal cord. Amiloride given at 5 mg/kg, 2 hrs before each PTX treatment was found to have moderate but significant effect in ameliorating mechanical allodynia and reducing astrogliosis in the spinal cord. Taken together, the experiments in this thesis provide in vitro and in vivo models to test drugs against PTX-induced neurotoxicity and present some evidence of amiloride’s potential use to treat PTX-induced peripheral neuropathy. However, further work is required to understand the mechanisms underlying amiloride effects in CIPN, and its drug safety profile in models of cancer. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350-word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………….. …………………………………….. …………………………………….. Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: i Copyright Statement ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350-word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed: …………………………………….. Date: …………………………………….. Authenticity Statement ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital formal.’ Signed: …………………………………….. Date: …………………………………….. ii Originality Statement ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by other, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistant from others in the projects design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed: …………………………………….. Date: …………………………………….. iii Acknowledgments I would first like to thank my supervisor, Dr Gila Moalem-Taylor, for letting me into her lab during Honours year and allowing me to continue through to Masters. Without her guidance this thesis would not have been possible, nor would I have been able to navigate the world of research as a new initiate. Her advice and comments have boosted my confidence and communication skills, which have helped me in both my professional and personal life. I would like to thank Dr Justin Lees, without whom I would have been very much lost indeed. His support and guidance in the lab and office have been indispensable and he very well may have taught me most of the practical skills I have. Thank you for letting me ask dumb questions and being so involved in this project, and for being a great mentor despite my vocal and your auricular inadequacies. I could not have asked for better or more supportive supervisors. My co-supervisor, Dr Patsie Pollie – we could not work together too much but I appreciated running into you and giving updates and planning potential studies. I am grateful to all members of my lab group for helping me with my experiments and for making this degree bearable. I have learned many things from meeting all of you and overall it has been a fascinating and educational experience. I want to thank all my friends, old and new, who have pushed me to be my best person and grounded me in times of need. They have helped me grow as a person through chocolates and chai, shared experiences and explorations of the unknown, and have been instrumental in shaping my choices in life. I am forever grateful for their attention and their willingness to kick me into the sunlight, literally and figuratively. iv Of course, none of this would be possible without my parents, brothers and family (and my extended family, the Uyghur community). Their constant stream of support, prayers and food have kept me physically and spiritually nourished during these at-times- difficult years and I am forever grateful. Distance does not make a difference when family is always in the group chat and the letter box. I do not have the words to describe the all-encompassing type of support I have received, and how much I will do my best to give back soon. I am always grateful for the many shoulders I can metaphorically lean on. I would also like to acknowledge my three grandparents who passed away during my time at UNSW; they always believed in me and I will do my best to never let them down. Bismillāhi r-raḥmāni r-raḥīm. v Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of many chemotherapy regimens and is becoming a more prevalent issue as the longevity of cancer patients continues to increase. Sensory symptoms include neuropathic pain, paraesthesia and numbness, and usually spread in a glove-and- stocking distribution. At present, there are no effective medications to treat or prevent CIPN, and the mechanisms by which symptoms are induced have not been fully elucidated. Paclitaxel (PTX) is a commonly used chemotherapeutic that induces neuropathy in a high percentage of patients. The broad aim of this thesis was to establish a model of CIPN in vitro and in vivo and test clinically approved drugs for potential neuroprotective effects. Since the dorsal root ganglion (DRG) has been implicated in CIPN, we cultured dissociated primary DRG neurons from 5-week-old C57BL/6 mice and treated them with PTX to observe neurotoxic effects.

Load more

  163

Copy Link