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Novel Pharmacological Modulators of P2X7 Receptor

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Novel Pharmacological Modulators of P2X7 Receptor Novel Pharmacological Modulators of P2X7 receptor A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Kshitija Dhuna MSc, Guru Nanak Dev University, Punjab, India. School of Health and Biomedical Sciences College of Science, Engineering and Health RMIT University March,2019 Declaration I certify that except where due acknowledgement has been made, the work is that of the author alone; the work has not been submitted previously, in whole or in part, to qualify for any other academic award; the content of the thesis/project is the result of work which has been carried out since the official commencement date of the approved research program; any editorial work, paid or unpaid, carried out by a third party is acknowledged; and, ethics procedures and guidelines have been followed. I acknowledge the support I have received for my research through the provision of an Australian Government Research Training Program Scholarship. Kshitija Dhuna Date: 18/03/19 ii Acknowledgement It is an extreme pleasure to express my sincere gratitude to my worthy guide, Dr Leanne Stokes, for her guidance, encouragement and useful critiques of this research work. You enabled me to undertake one of the most rewarding journeys of my life. You encouraged me to aspire to achieve my goals. My thesis, and the achievements throughout my candidature, would not have been possible without you. I feel blessed that I was given the opportunity to work under the supervision of a person who is an excellent scientist, a great teacher and a beautiful human being. I feel short of words to express my thanks to my co-supervisor A/Prof Samantha Richardson, whose unconditional support and encouragement made it possible for this work to see the light of the day. You took me by my hand and led me to the finish line. Thank you. I am indebted to Dr Martin Stebbing, my associate supervisor, for providing all the essential amenities for this project and for continuous and active involvement at each step of research work embodied in this thesis. I wish to convey my sincere thanks to Dr Ray M Helliwell, for making me a part of the ginsenosides story. Your in-depth knowledge of Pharmacology helped me thoroughly with all aspects of this project. Thank you! I would like to extend my gratitude to Dr Narin Osman for her constant words of encouragement and generous support during my entire candidature. Your smiles and reassurance helped me through some very difficult times. I would like to extend my heartfelt thanks to Dr Brett Cromer for his extensive help in the automated patch clamp experiments. iii The primary macrophage work in thesis would not have been possible without the generous contribution of Dr Simone de Luca and A/Prof Sarah Spencer who supplied the rat tissue for primary macrophage isolation. I am sincerely grateful to Prof Emilio Badoer and Dr Trisha Jenkins of the Neurobiology Research Group, thank you for your advice and support. I would also like to extend my gratitude to Dr Celine Velery, whose kind words made it a bit easier to survive this long journey. I would like to convey my sincere gratitude to members of the HDR administration team, Helen Cassidy and Mary Briganti. Thank you for answering the endless emails and also wiping away the occasional tears. I am grateful to our HDR co-ordinator, Prof Aj Jaworowski, for his support during my candidature. I would like to thank my friends at RMIT University, Saher Ali, Sefaa Al-Aryahi, Merfat Algathami and Durga Dharmadana for their friendship over the years. I would also like to mention the staff of Refuel cafeteria, who served coffee with a pinch of love! Thank you for making this journey less lonely. Thank you to my family for their outstanding support. Vikram, my husband, you stood by me through thick and thin like the Rock of Gibraltar. My beautiful daughter, Kainaat, your support and love made this thesis possible. My mother and sister, and my father in his time, without the constant support and help you graciously offered when I needed it; I could not have reached my goals. I acknowledge the support I have received for my research through the provision of an Australian Government Research Training Program Scholarship. iv Academic Contribution During the course of this thesis, the candidate’s aim was to contribute to the fields of Purinergic signalling and to characterise certain pharmacological modulators so as to attain a better insight into the P2X7 function and modulation. The candidate has contributed to the following publications and presentations: i. JOURNAL ARTICLES 1. Ginsenosides act as positive modulators of P2X4 receptors Kshitija Dhuna, Matthew Felgate, Stefan Bidula, Samuel Walpole, Lucka Bibic, Brett A. Cromer, Jesus Angulo , Julie Sanderson , Martin J. Stebbing, Leanne Stokes: Molecular pharmacology. 2018:mol.118.113696. 2. Neonatal overfeeding by small-litter rearing sensitizes hippocampal microglial responses to immune challenge: reversal with neonatal repeated injections of saline as well as minocycline Simone De Luca, Ilvana Ziko, Kshitija Dhuna, Luba Sominsky, Mary Tolcos, Leanne Stokes, Sarah Spencer: Journal of Neuroendocrinology 29(11):e12540 · October 2017. 3. P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology Leanne Stokes, Janice Layhadi, Lucka Bibic, Kshitija Dhuna, Samuel Fountain: Frontiers in Pharmacology 8 May 2017. 4. Selected ginsenosides of the protopanaxdiol series are novel positive allosteric modulators of P2X7 receptors. Ray M Helliwell, Charlene ShioukHuey, Kshitija Dhuna, Juan C Molero, Jiming M Ye, Charlene C Xue. British Journal of Pharmacology. 2015; 172(13):3326-40. v ii. CONFERENCE PRESENTATIONS 1. Ginsenosides cause cell death by potentiating calcium influx via P2X7 channels in a murine macrophage cell line. Kshitija Dhuna, Martin J Stebbing, Ray M Helliwell, Leanne Stokes, MGPCRS-ASCEPT, Melbourne, December 2016 2. Investigating the selectivity of ginsenoside positive modulators on P2X7 Kshitija Dhuna, Martin J Stebbing, Ray M Helliwell, Leanne Stokes, ASCEPT, Tasmania, December 2015 3. Minocycline: A novel pharmacological modulator of P2X7 Kshitija Dhuna, Martin J Stebbing, Leanne Stokes, GAGE conference, Canberra, April 2015 4. Minocycline modulates purinergic receptors Kshitija Dhuna, Martin J Stebbing, Leanne Stokes, HDR Conference, RMIT University, Melbourne, October 2014 vi TABLE OF CONTENT DECLARATION ...................................................................................................................... II ACKNOWLEDGEMENT ....................................................................................................... III ACADEMIC CONTRIBUTION .............................................................................................. V ABSTRACT ............................................................................................................................... 1 CHAPTER 1 .............................................................................................................................. 4 A REVIEW OF THE LITERATURE........................................................................................ 4 Introduction ................................................................................................................................ 4 1.1 Immune response: An overview ..................................................................................... 4 1.2 Initial recognition of danger: PAMPs and DAMPs ........................................................ 7 1.3 ATP: The endogenous “signal 0” ................................................................................. 10 1.4 ATP release from cells .................................................................................................. 11 1.5 Purinergic Signalling- An overview ............................................................................. 15 1.5.1 Discovery of Purinergic Signalling ................................................................................. 15 1.5.2 Classification and distribution of purinergic receptors ................................................... 15 1.5.3 Purinergic receptors in immune cells .............................................................................. 19 1.5.4 Role of ATP in short-term and long term (trophic) Purinergic Signalling ..................... 21 1.5.5 P2X receptors in macrophages and microglia ................................................................ 22 1.5.6 P2X7 receptor structure .................................................................................................. 24 1.5.7 Membrane pore formation by P2X7 receptors................................................................ 27 1.6 P2X7R in inflammation ..................................................................................................... 29 1.7 Pharmacological and therapeutic roles of P2X7 ................................................................ 31 1.8 Overall Aims ...................................................................................................................... 35 CHAPTER 2 ............................................................................................................................ 36 vii MATERIALS AND METHODS ............................................................................................. 36 Materials .................................................................................................................................. 36 2.1
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