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In Homogenized Rat Brain Tissue HEPOXILIN BINDING ACTMTY IN THE RAT BRAIN Melanie Kit Mei Yu A thesis submitted in conformity with the requirernents for the degree of Master of Science Graduate Department of Pharmacology University of Toronto O Copyright by Melanie Kit Mei Yu (1999) National Library Bibliothèque nationale I*l of Canada du Canada Acquisitions and Acquisitions et Bibliographie SeMces senkes bibliographiques 395 WeUingtori Street 395, rue Wellington Ottawa ON K1A ON4 OaawaON K1AON4 Canada Canada The author has granted a non- L'auteur a accordé une Licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distniute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfichelfilm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Hepoxilin binding activity in the rat brain Degree of Master of Science 1999 Melanie Kit Mei Yu Graduate Department of Pharmacology University of Toronto Previous work fiom our laboratory has shown that hepoxilins have neuromodulatory actions in the rat brain and that specific hepoxilin binding activities exist in hurnan neutrophils. In this study, we Uivestigate the existence of hepoxilin-specific binding in rat brain homogenates using HI-(~R)-HxA~M~, and the responsible protein. Specific binding was most abundant in the hippocampus and thalamus and the binding was tirne- and substrate-dependent with high affinity K43.1M.7 nM and B,42.3&7.3 pmoVmg of protein). Cornpetitive binding was best observed with unlabeled Ha,,HxB, and less with 1 1 ,12-EET. Binding studies of HxA, with îrozen sections and frozen homogenates using SDS-PAGE were inconclusive as a stronger signal was observed for nonspecific binding of the ligand. This unexpected observation may relate to the known instability of the hepoxilin binding protein in fiozen tissues. Results with fksh homogenates of brin suggest the presence of hitherto uncharacterized HxA, specific binding activity in rat brain. ACKNOWLEGEMENTS 1 would like to take this time to thank some people who have made my pursuit of graduate study successful. First of dl, thanks for Dr. Pace-Asciak for giving me the opportunity to work in his lab. His guidance and insight has contributed to the accompiishment of my work. 1 would aiso like to thank Dr. J. Nobrega, my advisor, for his help on my project; and Dr. C. Yip and Ms. Margaret Moule (Banting Institute) for making the use of the W light source available for photolabeling. In addition, grateful thanks go to my defense cornmittee, Dr. S. George, Dr. J. Nobrega, Dr. A. Okey and Dr. H. Yeger, for their time and suggestions. My deepest thanks are extended to my colleagues: Dr. Denis Reynaud for al1 kinds of help in the laboratory; Dr. Peter Demin, a great chemist, for his guidance in chemisv. Guidance and support fiom you al1 are well appreciated. Also, 1 would never forget al1 the foreign languages that I picked up from you dl! Thanks for dl the laughter and fun in these two years. 1 would also like to extend my gratitude to everyone in my family for their support, and love. To Mom and Dad, thanks for your endless concems, even though 1 made you mad sornetimes. To my brothers and sister, even you al1 are far away from me, your love will always be felt and remembered. And to Michael, your patience, encouragement and concerm during my study are greatly appreciated. Finally, 1 would like to thank the Research Institute, the Hospital for Sick Children for the financiai support during rny study. To ail the people I've forgotten, you will be always appreciated. And again, thanks everyone for making these two years mernorable! TABLE OF CONTENTS ABSTRACT ........................ ,....~...........~....................... ................................................ u.. ... ACKNOWLEDGEMENTS ..................................................m.........................................111 LIST OF FIGURES ....................................................................................................... vu... LIST OF TABLES ............................................................................................................ x LIST OF ABBREVIATIONS ......................................................................................... xi SECTION ONE: INTRODUCTION 1 .1 .1 Arachidonic acid .................................. ,.. ....................................................................... 1 1 .1.2 Arachidonic acid cascade ............................................................................................. 2 1.1.3 12-Lipoxygenase........................................................................................................ 4 1.2 HEPOXILINS ............................................................................................................ 4 1.2.1 Formation ....................................................................................................................... 4 1.2.2 Metabolism .............................................................................................................. 6 l .2.3 Biologicai actions ................................................................................................... 8 Actions in the central newous system ................................................................ 8 1.3 EKOSANOID RECEPTORS .................................................................................. 9 1.3.1 Eicosanoid receptors in the CNS ................................................................................. 1 1 PGD. receptoa (DF receptors) .....................................................................II PGE recepton (EP receptors) ........................................................................... 1 1 1.4 TEE BRAIN ............................................................................................................. 12 1.4.1 CerebeIlum................................................................................................................... 13 1.4.2 Diencephalon ................................................................................................................ 14 Thalamus .......................................................................................................... 14 Hypothalamus................................................................................................... 15 Hippocarnpus .................................................................................................... 16 1.5 RATIONALE AND OBJECTIVES ....................................................................... 18 Hypothesis ........................................................................................................ 18 SECTION TWO: MATERIALS AND METHODS 2.1 BINDING OF [3H]-(8R)-~MeIN HOMOGENIZED RAT BRAIN TISSUE ................................................................................................................................... 19 2.1.1 Materials ...................................................................................................................... 19 2.1.2 Brain tissue preparation ...............................................................................................19 2.1.3 Incubation with [~H]-(BR)-HxA~M~.......................................................................... 21 2.2 BINDING STUDIES IN HOMOGENIZED HIPPOCAMPUS AND THALAMUS ............................................................................................................ 21 2.2.1 Materials .......................... ,., ...................................................................................... 21 2.2.2 Brain tissue preparation ..............................................................................................22 2.2.3 Incubation with [~H]-(~R)-HxA~M~.......................................................................... 22 2.2.4 Statistics.................................................................................................................... 22 2.3 METABOLISM OF BxA, BY RAT BRAIN ............ ......m.....................................22 2.3.1 Materials ...................................................................................................................... 23 2.3.2 Brain tissue preparation ............................................................................................... 23 2.3.3 Incubation with [~H]-(~R)-HxA~M~or [~HI-(~R)-HXA~FA ..................................... 23 2.3.4 Extraction of samples ............................................................................................. 23 IODINATION OF ExA, PHOTOAFFINITY AZIDO ANALOG .............m........24 2.4.1 Materials .........................*............................................................................................24 2.4.2 Radio-iodination of HxA3-AZT .................................................................................. 24 2.4.3 Purification of (BS)-HXA~M~-[I~~I]-AZI .................................................................. 24 AUTORADIOGRAPHY OF
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