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Sigma Receptor Activation Mitigates Toxicity Evoked by The University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2015 Sigma Receptor Activation Mitigates Toxicity Evoked by the Convergence of Ischemia, Acidosis and Amyloid-beta Adam Alexander Behensky University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Neurosciences Commons, Pharmacology Commons, and the Physiology Commons Scholar Commons Citation Behensky, Adam Alexander, "Sigma Receptor Activation Mitigates Toxicity Evoked by the Convergence of Ischemia, Acidosis and Amyloid-beta" (2015). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/5641 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Sigma Receptor Activation Mitigates Toxicity Evoked by the Convergence of Ischemia, Acidosis and Amyloid-β by Adam A. Behensky A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences Department of Molecular Pharmacology and Physiology College of Medicine University of South Florida Major Professor: Javier Cuevas, Ph.D. Thomas E. Taylor-Clark, Ph.D. Jerome W. Breslin, Ph.D. Kay-Pong Yip, Ph.D. Mack H. Wu, MD Date of Approval: June 11, 2015 Keywords: intracellular calcium, whole-cell currents, ASIC1a, fluorescent imaging, stroke, vascular dementia © Copyright 2015, Adam A. Behensky ACKNOWLEDGMENTS First of all, I like to think my mentor, Dr. Javier Cuevas, for giving me the opportunity to become a scientist and future independent investigator. Through his support and mentorship I have thrived in the field of stroke research. I would also like to thank my committee members, Drs. Thomas Taylor-Clark, Jerome Breslin, Kay-Pong Yip and Mack Wu for their advice and support through these years. I would also like to extend thanks to my external examiner Dr. Donna Wilcock, for accepting to chair my dissertation committee and for her constructive criticism and comments on my dissertation. I would also like to thank Dr. Chris Katnik and Dr. Parmvir Bahia for providing advice and troubleshooting for various experiments and offer my thanks to Dr. Sarah Yuan, the chair of the Department of Molecular Pharmacology and Physiology, for all of her support as well as our department staff, Bridget Shields, Stacy Reed, Suzanne McMahon and Dr. Eric Bennett our department vice chair and PhD program director. Lastly, I would like to thank the vivarium staff, Haley, Karen and Jill for providing assistance with our experimental animals. This work was funded in part by a pre-doctoral fellowship from the American Heart Association to AAB (14PRE19570010). TABLE OF CONTENTS LIST OF TABLES ...................................................................................................... iv LIST OF FIGURES ...................................................................................................... v ABSTRACT ................................................................................................................. ix CHAPTER 1 Introduction ............................................................................................. 1 Significance ........................................................................................................... 1 Background ........................................................................................................... 2 Pathobiology of Ischemic Stroke ........................................................................... 4 Amyloid-β .............................................................................................................. 7 Microglia ................................................................................................................ 9 Sigma Receptors ................................................................................................. 11 Afobazole ............................................................................................................ 14 CHAPTER 2 In Vitro Evaluation of Guanidine Analogues as Sigma Receptor Ligands for Potential Anti-Stroke Therapeutics .......................................... 17 Introduction ......................................................................................................... 17 Materials and Methods ........................................................................................ 19 Preparation of Cortical Neurons ................................................................. 19 Calcium Imaging ........................................................................................ 20 In Vitro Competition Binding Assays .......................................................... 21 Primary Cultures of Microglia ..................................................................... 21 Microglia Migration ..................................................................................... 22 Drugs and Chemicals................................................................................. 23 Data Analysis ............................................................................................. 24 Results ................................................................................................................ 24 Discussion ........................................................................................................... 39 CHAPTER 3 Afobazole Activation of Sigma-1 Receptors Modulates Neuronal Responses to Amyloid-β25-35 ...................................................................... 45 Introduction ......................................................................................................... 45 Materials and Methods ........................................................................................ 48 Preparation of Rat Cortical Neurons .......................................................... 48 Calcium Imaging ........................................................................................ 49 ROS and NO Imaging ................................................................................ 49 Cytotoxicity Assay ...................................................................................... 50 Immunocytochemistry ................................................................................ 51 i Compounds, Reagents and Antibodies...................................................... 52 Data Analysis ............................................................................................. 52 Results ................................................................................................................ 52 Discussion ........................................................................................................... 66 CHAPTER 4 Stimulation of Sigma Receptors With Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-β25-35 .................... 72 Introducation ....................................................................................................... 72 Materials and Methods ........................................................................................ 74 Primary Cultures of Microglia ..................................................................... 74 Membrane Morphology and Migration Assay ............................................. 75 Calcium Imaging Measurements ............................................................... 76 ROS and NO Imaging ................................................................................ 77 Cell Death Assay ....................................................................................... 77 Immunocytochemistry ................................................................................ 78 Reagents and Antibodies ........................................................................... 79 Data Analysis ............................................................................................. 79 Results ................................................................................................................ 79 Discussion ........................................................................................................... 94 CHAPTER 5 Activation of Sigma Receptors via Afobazole Modulates Microglial but not Neuronal Apoptosis-Related Gene Expression in Response to Long-Term Ischemia Exposure ........................................................... 101 Introduction ....................................................................................................... 101 Materials and Methods ...................................................................................... 103 Primary Cultures of Microglia ................................................................... 103 Preparation of Cortical Neurons ............................................................... 104 Live/Dead Cell Assay ............................................................................... 104 Immunocytochemistry .............................................................................. 105 Calcium Imaging ...................................................................................... 106 Compounds, Reagents and Antibodies.................................................... 107 Data Analysis ..........................................................................................
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