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A Novel Compound Targeting Microglial Activation

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A Novel Compound Targeting Microglial Activation A NOVEL COMPOUND TARGETING MICROGLIAL ACTIVATION INAUGURAL-DISSERTATION TO OBTAIN THE ACADEMIC DEGREE DOCTOR RERUM NATURALIUM (DR. RER. NAT.) SUBMITTED TO THE DEPARTMENT OF BIOLOGY, CHEMISTRY AND PHARMACY OF FREIE UNIVERSITÄT BERLIN BY PHILIPP JORDAN aus Beckum, Deutschland 2018 This work was carried out at the Max-Delbrück-Centrum für Molekulare Medizin in the Helm- holtz Association from November 2013 to September 2017 under the supervision of Prof. Dr. Helmut Kettenmann and Dr. Susanne Wolf. 1st Reviewer: Prof. Dr. Udo Heinemann Max-Delbrück-Centrum für Molekulare Medizin Macromolecular Structure and Interaction Robert Rössle Str. 10 13125 Berlin 2nd Reviewer: Prof. Dr. Helmut Kettenmann Max-Delbrück-Centrum für Molekulare Medizin Cellular Neurosciences Robert Rössle Str. 10 13125 Berlin Date of defense: 20.03.2019 i ACKNOWLEDGEMENTS I thank Prof. Dr. Helmut Kettenmann for the opportunity to work on this fantastic project, for the supervision and funding, and to work in such a wonderful lab. Thanks to Prof. Dr. Udo Heinemann for being my university supervisor. I am very grateful for invaluable support and supervision from Dr. Susanne Wolf for the excellent supervision, many discussions and ideas and a lot of support through the development of this project, as well as for critical comments on this thesis. Furthermore, I would like to the thank the FMP screening unit of Jens Peter von Kries for the help in realisation the high throughput screen, the “Medicinal Chemistry” of Marc Nazaré for the help in chemical questions, in particular Edgar Specker, who was of great help identifying the chemical structures of compound C1.0 and the setting up the SAR for compound C4.0. Thanks to Matthias Endres and Golo Kronenberg for providing the stroke mouse model and Amanda Costa, who did the behavioural experiments. Special thanks to the wonderful technicians, Regina Piske and Maren Wendt for the help throughout the years with all experiments, Irene Haupt for the preparation of a tremendous amount of microglia for the high throughput screen, and all other technicians and Azubis who help to make the life of an PhD student easier. Special thanks to Birgit Jarchow for her support and invaluable help in all organisational matters and bureaucratic challenges. I would also particularly like to thank all my fellow PhD students, without whom the last years would have not been the same. It has been an amazing time, with help and support both intel- lectually and socially. Thanks especially to Petya Georgieva, Maria Pannell, Daniele Mattei, Felipe Sassi, Nadine Richter, Dong Le, Feng Hu, and Masataka Ifuku, as well as Alice Buonfigl- ioli, Amanda Costa, Dilansu Güneykaya, Verena Haage, Francesca Logiacco, Meron Maricos, Niklas Meyer, Stefan Wendt, and Olga Bakina (and everyone else who I forgot to mention here!). It was a wonderful time with you all. This thesis is dedicated to my whole family: Ingrid und Claus, Carsten, Catharina, and Victoria. You have been there for me whenever and wherever needed with support and understanding. Without you I wouldn’t be there where I am right now. ii TABLE OF CONTENTS Acknowledgements ........................................................................................................................... ii List of abbreviations ...................................................................................................................... viii List of figures .....................................................................................................................................x List of tables ................................................................................................................................... xiii 1 Introduction ............................................................................................................................ 1 1.1 A small history of microglia ......................................................................................... 1 1.1.1 Origin ............................................................................................................... 1 1.1.2 Capabilities ...................................................................................................... 2 1.1.3 Physiology ........................................................................................................ 2 1.1.4 Pathophysiology ............................................................................................... 3 1.2 Nitric Oxide .................................................................................................................. 3 1.2.1 The history as a biologically active molecule. ................................................ 3 1.2.2 The unique properties as a biological messenger .......................................... 4 1.2.3 Nitric oxide synthesis: Isoforms and mode of action ..................................... 5 1.2.4 The biological function of nitric oxide ............................................................ 6 1.2.5 Regulation of iNOS .......................................................................................... 7 1.3 Nitric Oxide in Stroke .................................................................................................. 9 1.3.1 Stroke – an overview ....................................................................................... 9 1.3.2 The double role of nitric oxide in stroke ........................................................ 9 1.3.3 Treatment of Stroke ...................................................................................... 11 1.4 Aim of this thesis ........................................................................................................ 11 2 Material and Methods .......................................................................................................... 13 2.1 Material ...................................................................................................................... 13 2.1.1 Chemicals and reagents ................................................................................ 13 2.1.2 Buffers ............................................................................................................ 14 2.1.3 Commercial kits ............................................................................................. 15 iii 2.1.4 Primer ............................................................................................................ 15 2.1.5 Tools and plasticware .................................................................................... 15 2.1.6 Devices ........................................................................................................... 16 2.1.7 Software ......................................................................................................... 17 2.2 Methods ....................................................................................................................... 17 2.2.1 Mice ................................................................................................................ 17 2.2.2 Primary cultured cells ................................................................................... 18 2.2.3 Immortalised cell lines .................................................................................. 20 2.2.4 Nitric Oxide quantification ........................................................................... 21 2.2.5 AlamarBlue assay ......................................................................................... 21 2.2.6 Enzyme-linked Immunosorbent Assay ........................................................ 22 2.2.7 Microchemotaxis assay ................................................................................. 23 2.2.8 Propidium iodide based proliferation and cell death assay ........................ 24 2.2.9 Flow cytometry .............................................................................................. 25 2.2.10 Quantitative PCR .......................................................................................... 26 2.2.11 High throughput screening (HTS) ................................................................ 27 2.2.12 Enzymatic activity assay .............................................................................. 29 2.2.13 Intravenous Pharmacokinetic Study in Mice .............................................. 30 2.2.14 Middle cerebral artery occlusion .................................................................. 30 3 Results ................................................................................................................................... 33 3.1 Screening for compounds inhibiting nitric oxide release in microglia .................... 33 3.2 Four compounds decrease the LPS induced NO release. ........................................ 43 3.3 The NO release is regulated independently from the pro-inflammatory stimulus.48 3.3.1 IFNγ induced NO release is regulated in a dose dependent manner in primary microglia .......................................................................................... 48 3.3.2 PolyIC induced NO release is regulated in a dose dependent manner in primary microglia. ......................................................................................... 50 3.4 Selective regulation of LPS induced, IL1β, IL6, and TNFα release in primary microglia. .................................................................................................................... 52 iv 3.4.1 Selective
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