Glycerophospholipids in Brain Phospholipases A 2 in Neurological Disorders Akhlaq A. Farooqui Lloyd A. Horrocks Glycerophospholipids in the Brain Akhlaq A. Farooqui and Lloyd A. Horrocks Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, U.S.A. Glycerophospholipids in the Brain Phospholipases A in Neurological Disorders 2 Akhlaq A. Farooqui Lloyd A. Horrocks, Ph.D. 3120 Herrick Road Department of Molecular and Cellular Columbus, OH 43221 Biochemistry USA The Ohio State University Columbus, Ohio 43210-1218 USA Preface Glycerophospholipids are amphipathic molecules that form the backbone of biological membranes, which are organized in bilayers and held together by hydrophobic, coulombic, and Van der Waal forces, and by hydrogen bonds. Biomembranes contain microdomains or lipid rafts that are rich in sphingolipids and cholesterol and serve as mobile platforms for signal transduction by cluster- ing and organizing bilayer constituents including receptors, enzymes, and ion- channels. Thus, biomembranes are not simply inert physical barriers but are complex dynamic environments that regulate cellular function by modulating activities of membrane-bound enzymes, receptors, and ion channels. Major advances in our understanding of signal transduction processes have occurred in last 20 years. A literature search on PubMed using the key word brain plus another key word illustrates the rapidly increasing interest in phospholipids and their metabolism in the brain (Table P-1). Although changes in the style of indexing at PubMed may skew these results, certainly the interest of researchers on phospholipids and phospholipases in the 5-year period increased at least 5-fold. The greatest increase was 14-fold for plasmalogen, indicating the realiza- tion of the very rapid turnover of these compounds and the role of choline plas- malogens (plasmenylcholine) as precursors of signaling molecules. We anticipate that this interest in research on brain phospholipids and phospholipases will con- tinue at a rapid rate in coming years as more information on the composition of glycerophospholipid molecular species and the involvement of phospholipases in normal brain and the pathophysiology of neural trauma and neurodegenerative diseases becomes available. Lipidomics and proteomics have emerged rapidly for the full characterization of the molecular species of phospholipids and for the enzymes associated with their metabolism. These techniques will be applied not only in whole brain, but also in neural membranes at cellular and subcellular levels as well as in biological fluids. These studies will help to understand the roles of phospholipid molecular species in gene expression, neural cell proliferation and differentiation, apoptosis, and maintenance of protein structure and function in normal brain, as well as in brain tissue from patients with neurological disorders. The phospholipases A2 are a superfamily of enzymes that hydrolyze arachidonic acid and docosahexaenoic v vi Preface TABLE P-1. PubMed search for papers with brain plus another keyword by year. Other Keyword, Year 2000 2001 2002 2003 2004 Phospholipids 446 516 354 2871 5251 Phosphatidylcholine 136 141 79 714 1338 Plasmalogen 13 20 18 128 183 Phospholipase 268 293 236 763 2022 Phospholipases 186 211 171 594 1412 Phospholipase A 70 84 78 256 691 2 Phospholipase C 153 155 119 349 1092 This search was done on 31 March 2006. acids from glycerophospholipids. These enzymes are involved in signal trans- duction, membrane homeostasis and remodeling, and neurodegeneration. The main purpose of this book is to present readers with cutting edge information on glycerophospholipids and phospholipases A and the generation of second mes- 2 sengers such as arachidonic and docosahexaenoic acids and their oxygenated metabolites (eicosanoids and docosanoids) in normal brain and brain from patients with neurological disorders. We attempt this in a form that is useful to students, teachers, and physicians, and to researchers in basic sciences, medicine, and the pharmaceutical industry. This book covers the involvement of phospholipases A in 2 neural trauma and neurodegenerative diseases and the therapeutic effects of phos- pholipase A inhibitors in neurological disorders. These topics are of immense 2 interest to neurochemists, neurologists, neuropharmacologists, and neurobiologists. The book has 14 chapters. The first two chapters describe the metabolism of glyc- erophospholipids in brain, including those containing a vinyl ether group (plasmalo- gens). Chapters 3 and 4 cover innovative information on the properties and roles of phospholipases A in the central nervous system. Chapters 5, 6, 7, 8, and 9 are devoted 2 to the release of second messengers, such as arachidonic acid, docosahexaenoic acid, lyso glycerophospholipids, and lysophosphatidic acid, from neural membrane glyc- erophospholipids by phospholipases A and their neurochemical effects on brain 2 metabolism and function. Chapters 10 and 11 cover the involvement of phospholi- pases A in neurological disorders, and the use of phospholipase A inhibitors for the 2 2 treatment of diseases associated with altered phospholipid metabolism. Chapter 12 describes the strengths and pitfalls of available methods for the assays of phospholi- pases A . Chapter 13 describes the association of phospholipases A with neuropsy- 2 2 chiatric disorders. Chapter 14 presents readers with future directions to follow to solve unresolved problems of brain phospholipid metabolism. Our choices of these topics are personal. They are based on our interests on phospholipid metabolism and phos- pholipases A and on areas where major progress is being made. We hope that our 2 attempt to consolidate the knowledge of glycerophospholipid metabolism and phos- pholipases A in brain will provide the basis of more dramatic advances and devel- 2 opments on the roles of glycerophospholipid molecular species in the brain and on the consequences of altered glycerophospholipid metabolism in neurological disorders. Akhlaq A Farooqui Lloyd A Horrocks Contents 1. Phospholipid Metabolism in Brain 1 1.1. Introduction 1 1.2. Classes, occurrence, and distribution of neural glycerophospholipids 3 1.3. Biosynthesis of neural membrane glycerophospholipids 4 1.4. Incorporation of glycerophospholipids into neural membranes 8 1.5. Effect of structural variations of glycerophospholipids on neural membrane structure 10 1.6. Catabolism of neural membrane glycerophospholipids 12 1.7. Phospholipid metabolism in the nucleus 14 1.8. Roles of glycerophospholipids in brain metabolism 16 1.8.1. Glycerophospholipids as a storage depot for second messengers and their precursors 16 1.8.1a. PLA2-generated second messengers 16 1.8.1b. PLC-generated second messengers 18 1.8.1c. PLD-generated second messengers 18 1.8.2. Involvement of PtdSer and PtdEtn in apoptosis 19 1.8.3. Phosphatidylinositol and membrane anchoring 21 1.8.4. Involvement of glycerophospholipids in regulation of enzymic activities 22 1.8.5. Other roles of glycerophospholipids 23 1.9. Conclusion 23 2. Ether Lipids in Brain 35 2.1. General considerations and importance 35 2.2. Plasmalogens 37 2.2.1. Biosynthesis 37 2.2.2. Receptor-mediated degradation 38 2.2.3. Roles of plasmalogens in brain tissue 42 2.2.3a. Plasmalogens as structural components of neural membranes 43 vii viii Contents 2.2.3b. Plasmalogens as a storage depot for second messengers 43 2.2.3c. Plasmalogens and generation of long-chain aldehydes 44 2.2.3d. Plasmalogens and membrane fusion 45 2.2.3e. Plasmalogens and ion transport 45 2.2.4. Plasmalogen, cholesterol efflux, and atherosclerosis 46 2.2.5. Plasmalogens and their antioxidant activity 47 2.2.6. Plasmalogens in differentiation 48 2.3. Platelet-activating factor (PAF) 48 2.3.1. PAF biosynthesis 50 2.3.2. PAF degradation 51 2.3.3. Roles of PAF 52 2.4. Antitumor ether lipids 53 2.5. Other ether lipids 55 2.6. Conclusion 56 3. Phospholipases A in Brain 67 2 3.1. Introduction 67 3.2. Multiplicity and properties of phospholipase A in brain tissue 68 2 3.2.1. sPLA 68 2 3.2.2. cPLA 71 2 3.2.3. PlsEtn-selective PLA 76 2 3.2.4. iPLA 77 2 3.3. Platelet-activating factor acetylhydrolases (PAF-AH) 80 3.4. Other brain phospholipases A 81 2 3.5. Brain nuclear PLA activities 82 2 3.6. Regulation of isoforms of PLA in brain tissue 83 2 3.7. Conclusions 85 4. Roles of Phospholipases A in Brain 93 2 4.1. PLA isoforms and neurotransmitter release 94 2 4.2. PLA isoforms in long-term potentiation (LTP) 95 2 4.3. Involvement of PLA isoforms in membrane repair 97 2 4.4. PLA isoforms in modulation of neurite outgrowth 2 and regeneration 98 4.5. PLA isoforms in inflammatory and anti-inflammatory 2 processes 100 4.6. Involvement of PLA isoforms in the cell cycle 102 2 4.7. PLA isoforms in tubule formation and membrane trafficking 102 2 4.8. PLA isoforms in neurodegeneration 104 2 4.8.1. Involvement of PLA isoforms in apoptosis 105 2 4.8.2. Involvement of PLA isoforms in necrosis 109 2 5. Arachidonic Acid and Its Metabolites in Brain 121 5.1. Introduction 121 Contents ix 5.2. Incorporation of arachidonic acid and docosahexaenoic acid into neural membranes 122 5.3. Receptor-mediated release of arachidonic acid 124 5.4. Neurotrophic effects of arachidonic acid 129 5.5. Neurotoxic effects of arachidonic acid 131 5.6. Metabolism of arachidonic acid in brain 132 5.7. Importance of eicosanoids in brain 135 6. Docosahexaenoic Acid and Its Metabolites in Brain 147 6.1. Location and turnover of docosahexaenoic acid 147 6.2. Incorporation of docosahexaenoic acid 149 6.3. Receptor-mediated release of docosahexaenoic acid from glycerophospholipids 151 6.4. Effects of DHA and its metabolites on brain tissue 153 6.4.1. DHA in gene expression, neurotransmitter release, and enzyme regulation 154 6.4.2. DHA and neurite outgrowth 156 6.4.3. DHA and modulation of learning and memory 157 6.4.4. DHA and apoptotic cell death 158 6.4.5. DHA and generation of docosanoids 159 6.4.6. DHA and the immune response 160 6.4.7. DHA intake, oxidative stress, and other side effects 162 7. Nonenzymic Metabolites of Arachidonate and Docosahexaenoate in Brain 173 7.1. Introduction 173 7.2. Reactive oxygen species 173 7.3. Lipid hydroperoxides 177 7.4. Isoprostanes, isofurans, isothromboxanes, isoleukotrienes, and neuroprostanes 178 7.4.1. Isoprostanes 178 7.4.2. Isothromboxanes 182 7.4.3. Isofurans 183 7.4.4. Isoleukotrienes 184 7.4.5. Neuroprostanes 184 7.4.5. Neuroketals 184 7.5. Generation of 4-HNE and its effect on brain metabolism 185 7.5.1. 4-HNE is a signaling molecule 185 7.5.2. Neurotoxic effects 186 7.6. Effects of acrolein in brain 188 7.7. Generation of DHA metabolites and their effect on brain metabolism 189 7.7.1. Neurotrophic effects of DHA 189 7.7.2. Neurotoxic effects of DHA 190 7.8. Effects of nonenzymic degradation of LA on brain metabolism 190 x Contents 8. Lyso-Glycerophospholipids 199 8.1. Introduction 199 8.2. Effects of lyso-glycerophospholipids on neural membrane metabolism 201 8.2.1. 1-Acyl-2-lyso-sn-GroPCho (Lyso-PtdCho) 201 8.2.2. Lyso-PtdEtn 206 8.2.3. Lyso-PtdSer 206 8.2.4. Lyso-PtdIns 208 8.2.5. Lyso-PlsEtn and lyso-PlsCho 208 8.3. Lyso-phospholipases in brain 209 8.4. Lyso-plasmalogenase in brain 211 8.5. Concluding remarks 212 9. Lysophosphatidic Acid and Its Metabolism in Brain 219 9.1. Functions of lysophosphatidic acid in brain 219 9.2. Synthesis and degradation of lyso-PtdH 220 9.3. LPA receptors and Lyso-PtdH-mediated signaling in brain 222 9.4. Agonists and antagonists of LPA receptors 225 9.5. Lyso-PtdH and its receptors in neurological diseases 229 9.6. Lyso-PtdH and its receptors in non-neural diseases 230 10. Involvement of Phospholipids and Phospholipases A 2 in Neurological Disorders 239 10.1. Introduction 239 10.2. Similarities and differences between acute neural trauma and neurodegenerative diseases 239 10.3. Involvement of excitotoxicity and glycerophospholipid degradation mediated by PLA in acute neural trauma and 2 neurodegenerative diseases 241 10.3.1. PLA activity in neurological disorders 243 2 10.3.2. PLA in ischemic injury 247 2 10.3.3. PLA in Alzheimer disease 250 2 10.3.4. PLA in Parkinson disease (PD) and its 2 animal models 254 10.3.5. PLA in multiple sclerosis (MS) and experimental 2 autoimmune encephalomyelitis (EAE) 255 10.3.6. PLA in prion diseases 257 2 10.3.7. PLA in spinal cord injury 258 2 10.3.8. PLA in head injury 259 2 10.3.9. PLA in epilepsy 259 2 10.4. Excitotoxicity-mediated neurodegeneration involves PLA 2 activation, generation of lipid mediators, oxidative stress and neuroinflammation 260