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SPHINGOSINE KINASE INHIBITION AMELIORATES CHRONIC HYPOPERFUSION-INDUCED WHITE MATTER LESIONS 112 4.1 Introduction

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SPHINGOSINE KINASE INHIBITION AMELIORATES CHRONIC HYPOPERFUSION-INDUCED WHITE MATTER LESIONS 112 4.1 Introduction SPHINGOSINE KINASE INHIBITION AMELIORATES CHRONIC HYPOPERFUSION- INDUCED WHITE MATTER LESIONS YANG YING (B.Sc. (Hons.), Zhejiang University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY YONG LOO LIN SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2016 DECLARATION I hereby declare that the thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. _________________ Yang Ying 20 January 2016 I ACKNOWLEDGEMENTS First of all, I would like to express my deepest gratitude to my supervisor Prof. Peter Wong Tsun Hon for their continuous support during the past five years of my PhD study. Without his guidance and help, it is impossible for me to fulfil my research work and complete this thesis. The scientific advice and insightful discussions he provided about my research benefit me greatly. His patience, motivation and immense knowledge always inspire me greatly. Prof Wong has been so supportive and has given me much freedom to pursue various research ideas without objection. Besides, he provided me many opportunities to attend workshops, International conferences, which has been very helpful in broadening my vision. I’m also extremely grateful to my Co-supervisor Dr. Lai Kim Peng Mitchell for his enlightening ideas, invaluable scientific advice and continuous support. His enthusiasm, extraordinary kindness and patience impressed me a lot. I’m also very grateful for introducing me collaborators and always encourage me when I met with difficulties. This thesis could not have been written without his valuable suggestions. I would like to extend my heartfelt gratitude to all the lab members, past and present, for their help along these years. My sincere appreciation first goes to Mrs. Ting Wee Lee for her great work and patient assistance on administrative stuffs, such as reagents ordering, paper work filing and keeping the lab tidy and organized. Also I would like to express my gratitude to Ms Wu Qi, Mr Zhao Heng and Ms Chan Sujing for their guidance and technical support in the early years of my PhD as well as their warm II friendship. Genuine appreciation to Ms Zhao Huiand Ms Nur-Ezan Mohamed for their warm friendship. Special thanks to Dr. Federico Tesio Torta, and Dr. Pradeep Narayanaswamy for their technical support and scientific suggestions on the collaborations in lipidomics analysis. Many thanks to my friends for their constant encouragement thoughout these years. Finally, I owe my gratitude to my family members. Their love and encouragement always support me to overcome difficulties. III TABLE OF CONTENTS SUMMARY ................................................................................................ VII LIST OF TABLES .......................................................................................IX LIST OF FIGURES ...................................................................................... X ABBREVIATIONS .................................................................................... XII PUBLICATIONS ....................................................................................... XV CHAPTER 1 INTRODUCTION 1 1.1 Vascular cognitive impairment .................................................. 1 1.1.1 Definition of VCI ................................................................... 1 1.1.2 Vascular neuropathological substrates ................................... 1 1.1.3 Risk factors ............................................................................ 5 1.1.4 Diagnosis ............................................................................... 7 1.1.5 Therapeutic implications ........................................................ 8 1.1.6 Symptomatic treatment .......................................................... 9 1.2 Mechanisms of white matter lesions ....................................... 10 1.2.1 Composition of cerebral white matters ................................ 11 1.2.2 Pathophysiology of WML ................................................... 26 1.2.3 Animal models of WML ...................................................... 36 1.3 Sphingosine-1-phosphate: A Bioactive Sphingolipid ............ 40 1.3.1 S1P synthesis and degradation ............................................. 40 1.3.2 S1P regulating cell fate: an Intracellular Mediator: ............. 48 1.3.3 S1P receptors ....................................................................... 49 1.3.4 S1P receptors in the brain .................................................... 49 1.3.5 SphK/S1P/S1PR signaling in regulation oligodendroglial lineage cells ............................................................................................ 50 1.3.6 SphK/S1P/S1PR signaling in hypoxia/ischemia .................. 52 1.4 Research rationale and objectives ........................................... 53 CHAPTER 2 METHOD AND MATERIAL ......................... 55 2.1 Animal ..................................................................................... 55 2.2 Bilateral common carotid artery stenosis model (BCAS) ....... 55 2.3 Cerebral blood flow measurement ........................................... 57 2.4 Barnes maze ............................................................................. 58 2.4.1 Equipment and field setup ................................................... 58 2.4.2 Adaptation period ................................................................ 60 2.4.3 Spatial acquisition phase ...................................................... 61 IV 2.4.4 Probe trial ............................................................................. 61 2.4.5 Data analysis ........................................................................ 62 2.5 SKI-II Treatment ..................................................................... 63 2.6 Coronal brain slice Preparation ............................................... 63 2.6.1 Reagent ................................................................................ 63 2.6.2 Procedure ............................................................................. 63 2.7 White matter tissue isolation ................................................... 64 2.8 Kluver-Barrera staining ........................................................... 65 2.8.1 Reagent ................................................................................ 65 2.8.2 Procedure ............................................................................. 65 2.9 Immunofluorescence staining .................................................. 66 2.9.1 Reagent ................................................................................ 66 2.9.2 Procedure ............................................................................. 66 2.10 Microscopy .............................................................................. 66 2.11 Western blot analysis ............................................................... 67 2.11.1 Reagent ............................................................................. 67 2.11.2 Sample preparation ........................................................... 67 2.11.3 Western blot ..................................................................... 67 2.12 Lipid extraction ....................................................................... 68 2.12.1 Reagent ............................................................................. 68 2.12.2 Procedure .......................................................................... 69 2.13 Lipid analysis ........................................................................... 69 2.13.1 Reagent ............................................................................. 69 2.13.2 Phospholipid and sphingolipid ......................................... 69 2.13.3 S1P ................................................................................... 70 2.13.4 Cholesterol ....................................................................... 71 2.13.5 Lipidomics data processing .............................................. 71 2.14 Primary oligodendroglia lineage cell culture .......................... 71 2.14.1 Reagent ............................................................................. 71 2.14.2 Equipment setup ............................................................... 72 2.14.3 Dissection and plating and culture of neonatal rat cortices 72 2.14.4 OPC isolation and culture ................................................ 73 2.14.5 Chemical induction of hypoxia in vitro ........................... 74 2.15 Quantification of immunofluorescence staining ..................... 75 V 2.16 Statistical analysis ................................................................... 75 CHAPTER 3 THE LIPIDOME OF WHITE MATTER LESIONS IN MOUSE BRAIN INDUCED BY GLOBAL CHRONIC HYPOPERFUSION 80 3.1 Introduction ............................................................................. 80 3.2 Results ..................................................................................... 82 3.2.1 BCAS causes global CBF decrease and hypoxia in mouse brain 82 3.2.2 Selective White matter lesions induced by hypoperfusion .. 85 3.2.3 Cognitive impairment in BCAS mice .................................. 89 3.2.4 Lipids alterations .................................................................. 93 3.3 Discussion .............................................................................
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