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The Role of Prostaglandin H Synthase (Phs)

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The Role of Prostaglandin H Synthase (Phs) THE ROLE OF PROSTAGLANDIN H SYNTHASE (PHS) BIOACTIVATION AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2)-MEDIATED PROTECTION IN ENDOGENOUS AND METHAMPHETAMINE-INITIATED NEUROTOXICITY By Annmarie Ramkissoon A thesis submitted in the conformity with the requirements for the Degree of Doctor of Philosophy Graduate Department of Pharmaceutical Sciences University of Toronto © Copyright by Annmarie Ramkissoon 2011 THE ROLE OF PROSTAGLANDIN H SYNTHASE (PHS) BIOACTIVATION AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2)-MEDIATED PROTECTION IN ENDOGENOUS AND METHAMPHETAMINE-INITIATED NEUROTOXICITY Doctor of Philosophy, 2011 Annmarie Ramkissoon Graduate Department of Pharmaceutical Sciences University of Toronto ABSTRACT Endogenous brain compounds and xenobiotics, including the neurotoxins such as the amphetamine analogs 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), methamphetamine (METH, Speed) and methylenedioxyamphetamine (MDA, active metabolite of MDMA), may be bioactivated by prostaglandin H synthase (PHS) to free radicals that generate reactive oxygen species (ROS). In the absence of adequate antioxidant or repair mechanisms, ROS oxidize macromolecules such as DNA, protein and lipids, which can lead to toxicity. In vitro, we evaluated bioactivation using both purified ovine PHS-1 and cultured cells stably overexpressing either human PHS-1 or hPHS-2 isozymes. We found the neurotransmitter dopamine, its precursors and some metabolites, as well as METH and MDA, can be bioactivated by ovine and/or human PHS in an isozyme-dependent fashion that generates ROS, which oxidize DNA and protein and increase toxicity. This process is blocked by both the PHS inhibitor acetylsalicylic acid (ASA) and the ROS detoxifying enzyme catalase. Our data are the first to reveal isozyme-dependent bioactivation by PHS as a potential mechanism for enhanced susceptibility to both exogenous and endogenous neurotoxins, the latter of which may be particularly important in aging. METH-initiated ROS can also activate redox-sensitive transcription factors such as nuclear factor erythroid 2-related factor 2 (Nrf2), which is involved in the induction of an array of protective mechanisms in both adult and fetal brain. Using Nrf2 ii knockout mice, we showed Nrf2 has a novel neuroprotective role in METH-initiated oxidative stress, neurotoxicity and functional deficits in both fetal development and adulthood, especially with multiple exposures allowing time for the induction of neuroprotective mechanisms. Our studies are the first to show that Nrf2 afforded protection against both motor coordination deficits and olfactory deficits caused by METH in utero and in adults, suggesting that deficiencies in Nrf2 activation constitute a risk factor for ROS-mediated neurotoxicity in the fetus and adult. iii ACKNOWLEDGEMENTS I would like to thank Dr. Wells for the opportunity to work in his lab and for all the life lessons he has meticulously taught me over the years. I would also like to thank my advisory committee members, Drs. Catherine Bergeron, Stephen Kish, Jeffrey Henderson and Jack Uetrecht for their constructive criticism and for always challenging me to do more. Special thanks to Dr. Winnie Jeng for being a great mentor and who provided me a starting point for my thesis on PHS and encouraged me to think creatively and pursue other interests. Thanks to Dr. Luisa Goncalves for taking on the EPR studies while balancing her life in a new country with a new baby and to Dr. Tom Preston for all his advice about cell culture and encouraging me to work diligently. Thanks to Lily Morikawa from the Pathology Core, Toronto Centre for Phenogenomics, for her help with immunohistochemistry, the Uetrecht lab for use of their RT-PCR machine and Xiaochu Zhang for all the advice. Thanks to former undergraduate students Ada Ho and James Poon for being enthusiastic helpers. Also, thanks to all the members of the Wells lab and Henderson lab and special thanks to Crystal Lee and Kelvin Hui for being great role models. Their work ethic and integrity were very inspiring to me and helped me through the difficult times. I would also like to thank my friends, especially CT, HC, MW, TA, YZ, AS and MJ who provided me a variety of resources for entertainment. Last, but not least, I would like to thank my mom, dad and especially my brother whose Xbox and PlayStation kept me mentally sane throughout the years. iv TABLE OF CONTENTS CHAPTER 1: INTRODUCTION ........................................................................................ 1 1.1 RATIONALE, HYPOTHESIS AND OBJECTIVES .............................................. 2 1.1.1 RATIONALE ............................................................................................. 2 1.1.2 HYPOTHESIS AND OBJECTIVES ....................................................... 9 1.2 BRIEF OVERVIEW .................................................................................................. 12 1.2.1 ROS IN THE BRAIN ................................................................................. 12 1.2.1.1 Introduction to Reactive Oxygen Species ............................................ 12 1.2.1.2 Sources of Reactive Oxygen Species .................................................... 15 1.2.1.2.1 Mitochondria .......................................................................... 15 1.2.1.2.2 Enzymes .................................................................................. 17 1.2.1.2.3 Excitotoxicity .......................................................................... 22 1.2.1.2.4 Immune Response-Microglia ................................................ 23 1.2.1.3 Neuroprotective Mechanisms ............................................................... 24 1.2.1.3.1 Blood Brain Barrier ............................................................... 24 1.2.1.3.2 Antioxidant Mechanisms ...................................................... 25 1.3 PROSTAGLANDIN H SYNTHASES (PHSs) ......................................................... 33 1.3.1 ROLE OF PROSTAGLANDIN SYNTHESIS AND THEIR RECEPTORS ............................................................................................... 33 1.3.2 GENETICS OF PHS ................................................................................... 38 1.3.2.1 Genes ........................................................................................................ 38 1.3.2.2 Transcriptional regulation ..................................................................... 40 1.3.2.3 Post-transcriptional regulation ............................................................. 45 1.3.3 PRIMARY PROTEIN STRUCTURES OF PHSs .................................... 46 1.3.4 PHS ENZYMOLOGY ................................................................................. 49 1.3.5 INHIBITION OF PHSs ............................................................................... 53 1.3.6 CELLULAR LOCALIZATION AND CENTRAL NERVOUS SYSTEM (CNS) EXPRESSION OF PHSs ................................................ 57 1.3.7 PHS IN ROS GENERATION .................................................................... 59 1.3.8 PHS IN NEURODEGENERATIVE DISEASES ...................................... 64 1.4 NUCLEAR FACTOR ERYTHROID 2-RELATED FACTORS (NRFs) ................ 71 v 1.4.1 OVERVIEW OF NRF1, NRF2 AND NRF3 .................................................. 71 1.4.2 MECHANISM OF ACTION OF NRF2 ........................................................ 72 1.4.3 GENETICS OF NRF2 ..................................................................................... 75 1.4.4 PROTEIN STRUCTURE OF NRF2 .............................................................. 76 1.4.5 REGULATORS OF NRF2 ............................................................................. 80 1.4.5.1 Negative regulation by Kelch-like ECH-associated protein 1 (Keap1) ... 80 1.4.5.2 Negative regulation by proteasome degradation ....................................... 83 1.4.5.3 Regulation of transcriptional complex in nucleus ..................................... 84 1.4.6 ANTIOXIDANT RESPONSE ELEMENT (ARE) ....................................... 87 1.4.7 ACTIVATORS OF NRF2 ............................................................................... 91 1.4.8 NRF2 IN NEUROTOXICITY AND CNS DISEASES ................................. 95 1.4.8.1 Nrf2 expression ............................................................................................ 95 1.4.8.2 Nrf2 in neurodegenerative diseases ............................................................ 96 1.4.8.3 Nrf2 in chemical-induced neurotoxicities .................................................. 100 1.4.9 NRF KNOCKOUT MOUSE MODELS ........................................................ 102 1.4.10 EVIDENCE FOR POLYMORPHISMS IN THE KEAP1- NRF2-ARE PATHWAY ..................................................................................................... 104 1.5 METHAMPHETAMINE ............................................................................................... 107 1.5.1 HISTORY AND USES .................................................................................... 107 1.5.2 PHARMACOKINETICS ................................................................................ 110 1.5.3 DISTRIBUTION .............................................................................................. 112 1.5.4 METABOLISM BY CYTOCHROMES P450 (CYPs) and ELIMINATION .............................................................................................
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