Lipid Mediators and Their Metabolism in the Brain Akhlaq A. Farooqui Lipid Mediators and Their Metabolism in the Brain Akhlaq A. Farooqui Department of Molecular and Cellular Biochemistry The Ohio State University Columbus, OH 43210 USA [email protected] ISBN 978-1-4419-9939-9 e-ISBN 978-1-4419-9940-5 DOI 10.1007/978-1-4419-9940-5 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011934260 © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Dedicated to my teachers for their passion to teach and stimulate the desire to learn and integrate knowledge. Akhlaq A. Farooqui Preface Neural membranes are highly dynamic and interactive structures composed of glycerophospholipids, sphingolipids, cholesterol, and transmembrane and peripheral proteins of various shapes, molecular masses, and functions. The binding between phospholipids and proteins is necessary for vertical positioning and tight integration of proteins into the membrane. Phospholipids and sphingolipids contribute to the lipid bilayer asymmetry, whereas cholesterol and sphingolipids form lipid rafts, which act as platforms for molecular sorting, trafficking, and signal transduction processes. Lipid mediators are chemical messengers that are released in response to cell stimulation or injury from membrane phospholipids, sphingolipid, and choles- terol. Lipid mediators play important roles in internal and external communication and modulate cellular responses such as the growth arrest, differentiation, adhesion, and migration. These processes are modulated by eicosanoids (prostaglandins, leukotrienes, thromboxanes, and lipoxins) and docosanoids (resolvins, protectins, neuroprotectins, and maresins), which are generated by the action of phospholi- pases A2, cyclooxygenases, and lipoxygenases on arachidonic and docosahexaenoic acids (ARA and DHA), respectively. The non-enzymic lipid mediators of ARA and DHA metabolism include isoprostanes, neuroprostanes, isoketals, neuroketals, isofurans, 4-hydroxynonenal, and 4-hydroxyhexanal. Action of sphingomyelinases on sphingomyelin generates ceramide, a metabolite closely associated with apop- totic cell death. Further degradation of ceramide generates sphingosine, which in its phosphorylated form induces cell proliferation, and thus produces the balance between cell death and cell survival. In the brain, cholesterol is hydroxylated into oxycholesterols or hydroxycholesterols (24(S)-hydroxycholesterol, 25-hydroxyc- holesterol, 27-hydroxycholesterol, 22-hydroxycholesterol) by cytochrome P450- dependent oxygenases. Conversion of cholesterol to hydroxycholesterols is a major mechanism for the elimination of cholesterol from the brain. Collective evidence suggests that under normal conditions low levels of lipid mediators are needed for signal transduction, gene expression, and neural cell proliferation and differentia- tion, resulting in neural cell survival but high levels of enzymic and non-enzymic lipid mediators may cause neurodegeneration through the induction of oxidative stress, neuroinflammation, and apoptosis. Thus, neural membranes are not only vii viii Preface simple inert barrier, but a Pandora’s box of lipid mediators; many of which have powerful neurochemical effects on cell growth, proliferation, differentiation, survival, and apoptosis. Levels of lipid mediators in neural and non-neural tissues are partly regulated by diet. The high intake of food enriched in ARA (vegetable oils) elevates levels of eicosanoids and upregulates the expression of proinflamma- tory cytokines. ARA and its metabolites have prothrombotic, proaggregatory, and proinflammatory properties. In contrast, diet enriched in DHA (fish and fish oil) generates docosanoids, which not only downregulate proinflammatory cytokines but also have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory effects. At present, the threshold concentrations of lipid mediators that promote and facilitate neural cell injury and death are not known. In neurological disorders, cell death not only depends upon elevated levels of lipid mediators, but also on cross-talk (interplay) among glycerophospholipid-, glycosphingolipid-, and cholesterol-derived lipid mediators. Studies on lipid-derived mediators fall in a fast- paced research area related to neurodegeneration and provide opportunities for target-based therapeutic intervention using inhibitors of lipid mediator synthesizing enzymes. The goal of this monograph is to present readers with cutting edge and compre- hensive information on lipid mediators in a manner that is useful not only to stu- dents and teachers, but also to researchers and physicians. This monograph has 11 chapters. Chapters 1 and 2 describe metabolism, roles, and involvement of eico- sanoids and docosanoids in neurological disorders. Chapters 3 and 4 describe cutting edge information on the synthesis, degradation, roles, and association of lyso-glyc- erophospholipids and platelet activating factor in neurological disorders. Chapter 5 describes metabolism and roles of cannabinoids in brain and their relationship with neurological disorders. Chapters 6 and 7 are devoted to the metabolism of nonenzymic lipid mediators of arachidonic acid metabolism (4-hydroxynonenal and isopros- tanes) and docosahexaenoic acid metabolism (4-hydoxyhexanal and neuroprostanes). Chapters 8 and 9 describe metabolism, roles, and involvement of ceramide, cer- amide-1-phosphate, sphingosine, and sphingosine-1-phosphate, respectively, in neurological disorders. Chapter 10 describes metabolism, role, and association of cholesterol and hydroxycholesterols with neurological disorders. Finally, Chap. 11 provides readers and researchers with perspective that will be important for future research work on bioactive lipid mediators. My writing style and demonstrated ability to present complicated material on lipid mediators makes this monograph particu- larly accessible to neuroscience graduate students, teachers, and fellow researchers. It can be used as supplement text for a range of neuroscience courses. Clinicians and pharmacologists will find this book useful for understanding molecular aspects of lipid mediators in neurodegeneration in acute neural trauma (stroke, spinal cord trauma, and head injury) and neurodegenerative diseases (Alzheimer disease, Parkinson disease, and Huntington disease). To the best of my knowledge no one has written a monograph on the role of lipid mediators in the brain. This monograph will be the first to provide a comprehensive description of glycerophospholipid, sphingolipid, and cholesterol-derived mediators, their interactions with each others in normal brain and in brain tissue from neurological disorders. I also hope that this Preface ix monograph will provide senior researchers some guidance for overcoming problems on lipid mediator research that they are encountering in their laboratories. One of the hallmark of this monograph is the presentation of a unifying concept of lipid mediator-mediated signal transduction processes associated with excitotox- icity, oxidative stress, and neuroinflammation. The presentation of this monograph is based on uniformity and logical progression of subject from one topic to another with an extensive bibliography. For the sake of explanation, simplicity, and unifor- mity a large number of figures and line diagrams of signal transduction pathways with chemical structures of lipid mediators are also presented. It is hoped that my attempt to integrate and consolidate the knowledge of lipid mediators and signal transduction processes in normal and diseased brain will provide the basis of more dramatic advances and developments on the determination, characterization, and roles of glycerophospholipid-, sphingolipid-, and cholesterol-derived lipid mediators in neurological disorders. Columbus, OH Akhlaq A. Farooqui Acknowledgments I thank my wife, Tahira, for critical reading of the manuscript, providing colored figures, and useful discussion during the writing of this monograph. This monograph would not have been possible without her unrelenting support, constructive criti- cisms, and constant encouragement. I also thank Dr. Wei-Yi Ong, Department of Anatomy, National University of Singapore, Singapore, for many years of collabora- tion on phospholipases A2, lipid mediators, and their roles in neurodegeneration. Finally, I also express my gratitude to Ann H. Avouris and Melissa Higgs of Springer, New York, for their cooperation, rapid responses to my queries, and professional manuscript handing. It has been a pleasure working with them for many years. xi About My Teachers Late Professor Bimal Kumar Bachhawat was my Ph.D. advisor and Chief of Neurochemistry