Beneficial Effects of Fish Oil on Human Brain978-1-4419-0543-7/1.pdf · fish oil in human diet along with transport and importance of DHA in brain. Chapters 3 and 4 describe cutting-edge

Beneficial Effects of Fish Oil on Human Brain

Akhlaq A. Farooqui

Beneficial Effects of FishOil on Human Brain

1 3

Akhlaq A. FarooquiDepartment of Molecularand Cellular Biochemistry

The Ohio State UniversityColumbus, OH [email protected]

ISBN 978-1-4419-0542-0 e-ISBN 978-1-4419-0543-7DOI 10.1007/978-1-4419-0543-7Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2009929747

# Springer ScienceþBusiness Media, LLC 2009All rights reserved. This workmay not be translated or copied in whole or in part without the writtenpermission of the publisher (Springer ScienceþBusinessMedia, LLC, 233 Spring Street, NewYork,NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use inconnection with any form of information storage and retrieval, electronic adaptation, computersoftware, 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 theyare not identified as such, is not to be taken as an expression of opinion as to whether or not they aresubject to proprietary rights.While the advice and information in this book are believed to be true and accurate at the date ofgoing to press, neither the authors nor the editors nor the publisher can accept any legalresponsibility for any errors or omissions that may be made. The publisher makes no warranty,express or implied, with respect to the material contained herein.

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In the memory of my beloved uncle ‘‘lateMohd Ateeq Saheb’’ and grandmother ‘‘lateMasoodi Begum,’’ who brought me up, gaveme their unyielding support, and taught methe difference between right and wrong.

– Akhlaq A. Farooqui

Preface

In neural membrane glycerophospholipids, essential polyunsaturated fattyacids, namely arachidonic acid (ARA) and docosahexaenoic acid (DHA), areexclusively located at the sn-2 position of glycerol moiety. Because humans donot possess desaturases that insert either the n-3 or the n-6 double bonds, thesefatty acids are derived from diet. DHA can be obtained from fish or from theprecursor a-linolenic acid (ALA), which is found in nuts. The common pre-cursor for ARA is dietary linoleic acid (LA) from plant sources. The high intakeof food enriched in vegetable oils elevates levels of ARA-derived eicosanoidsand upregulates the expression of proinflammatory cytokines. ARA-derivedeicosanoids have prothrombotic, proaggregatory, and proinflammatory prop-erties. In contrast, a diet enriched in eicosapentaenoic acid (EPA) and DHA(fish and fish oil) generates docosanoids, which not only downregulate proin-flammatory cytokines but also have antiinflammatory, antithrombotic, antiar-rhythmic, hypolipidemic, and vasodilatory effects. Thus, levels of eicosanoidsand docosanoids in neural and non-neural tissues are partly regulated by diet.The present Western diet is deficient in DHA, but has high amounts of ARA.The deficiency of n–3 fatty acids in diet results in a number of abnormalities inanimals and human infants such as impaired vision, abnormal electroretino-gram, and several behavioral abnormalities. In addition, inclusion of n–3 fattyacids in diet not only prevents cardiovascular disease but also protects fromstroke, epilepsy, and other neurological and neurodegenerative diseases such asAlzheimer disease, Parkinson disease, and peroxisomal diseases.

There have been remarkable developments on DHA and ARA metabolismin brain in the past 20 years. The main objective of this book is to presentreaders with cutting-edge and comprehensive information on metabolism androles of neural membrane DHA in a manner that is useful not only to studentsand teachers but also to researchers, dietitians, nutritionists, and physicians.This monograph has 11 chapters. Chapters 1 and 2 describe the importance offish oil in human diet along with transport and importance of DHA in brain.Chapters 3 and 4 describe cutting-edge information on the release and catabo-lism of DHA in brain along with neurochemical effects of its lipid mediators.Chapter 5 describes roles of DHA in brain. Chapter 6 is devoted to alterationsin DHA with aging and consequences of DHA deficiency in brain. Chapters 7

vii

and 8 describe the status and therapeutic importance of DHA and EPA in acutemetabolic trauma (stroke), neurotraumatic disorders (spinal cord and headinjuries), and neurodegenerative diseases (Alzheimer disease, Parkinson dis-ease, Huntington disease). Chapter 9 describes the status and therapeuticimportance of DHA and EPA in neuropsychiatric disorders (schizophrenia,depression, bipolar disorders, and attention-deficit/hyperactivity disorder).Chapter 10 provides information on the importance of DHA and EPA inother neural (peroxisomal) and some non-neural (rheumatoid arthritis, cysticfibrosis, chronic obstructive pulmonary disease, dermatological conditions,and gastrointestinal disorders) diseases. Finally, Chapter 11 provides readersand researchers with perspective that will be important for future research workon DHA and EPA in brain tissue.

This monograph can be used as supplemental text for a range of neu-roscience and nutrition courses. Neurologists and nutritionists will find thisbook useful for understanding molecular aspects of DHA and EPAmetabolismin neurological disorders. To the best of my knowledge, no one has written amonograph on the role of DHA and EPA and their lipid mediators (docosa-noids) in brain tissue, and this monograph is the first to provide a comprehen-sive description of docosanoids and their interactions with ARA-derivedeicosanoids in normal brain and in brain tissue from patients with neurologicaldisorders. This monograph not only provides background and refresher infor-mation on DHA metabolism in brain for readers not working in the field offatty acid metabolism but also presents new knowledge on DHA-derived lipidmediators and therefore broadens our understanding of DHA function inhealth and neurological disorders. The monograph offers a thorough andunique overview of the neurobiology of n–3 and n–6 fatty acids and theirassociation with neurological disorders. It is anticipated that nutritionists andclinicians may gain insight into problems associated with nutrition in the 21stcentury and resolve difficulties experienced in their research on fatty acidmetabolism and DHA- and ARA-derived lipid mediators in their laboratories.

The choice of topics presented in this monograph is personal. It is based notonly onmy interest inDHA andARAmetabolism in neurological disorders butalso in areas where major progress has been made. I have tried to ensureuniformity in mode of presentation as well as a logical progression of subjectfrom one topic to another and have provided extensive bibliography. For thesake of simplicity and uniformity, a large number of figures and line diagramsof signal transduction pathways are also included. I hope that my attempt tointegrate and consolidate the knowledge of DHA metabolism and signal trans-duction processes in normal and diseased brain will provide the basis of moredramatic advances and developments on the determination, characterization,and roles of DHA- and ARA-derived lipid mediators in neurological disorders.

Akhlaq A. FarooquiColumbus, Ohio

viii Preface

Acknowledgments

I thank my wife, Tahira, for critical reading of this monograph, offering valu-able advice, and evaluation of subject matter. Without her help and participa-tion, this monograph neither could nor would have been completed. I alsothank my son, Siraj, for drawing chemical structures of lipid mediators andsignal transduction pathways associated with arachidonic acid and docosahex-aenoic acid metabolism. I would also like to express my gratitude to Ann H.Avouris of Springer, New York, for her able and professional manuscripthandling.

Akhlaq A. Farooqui

ix

Contents

1 Fish Oil and Importance of Its Ingredients in Human Diet. . . . . . . . . 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 n–3 Fatty Acids in Fish Oil Capsules and Krill Oil

Capliques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2.1 Availability of Purified Fish Oil and Krill Oil

Preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.2 Other n–3-Enriched Manufactured Products . . . . . . . . 8

1.3 Effects of Fish Oil on Human Health . . . . . . . . . . . . . . . . . . . 81.4 Effects of Fish Oil on Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1.4.1 Antiinflammatory and Antiatherosclerotic Effectsof Fish Oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1.4.2 Antiarrythmic Effects of Fish Oil . . . . . . . . . . . . . . . . . 111.4.3 Antithrombotic Effects of Fish Oil . . . . . . . . . . . . . . . . 131.4.4 Effect of n–3 Fatty Acids on Revascularization . . . . . . 141.4.5 n–3 or ! –3 Index and Heart Disease . . . . . . . . . . . . . . 15

1.5 Effects of Fish Oil on Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.5.1 Effect of Fish Oil on Neural Membranes . . . . . . . . . . . 161.5.2 Effect of Fish Oil on Neuritogenesis . . . . . . . . . . . . . . . 171.5.3 Effect of n–3 Fatty Acids on Ion Channels . . . . . . . . . . 171.5.4 Effect of n–3 Fatty Acids on Receptors . . . . . . . . . . . . 18

1.6 Effects of Fish Oil on Lungs. . . . . . . . . . . . . . . . . . . . . . . . . . . 181.7 Effects of Fish Oil on Kidneys . . . . . . . . . . . . . . . . . . . . . . . . . 191.8 Effects of Fish Oil on Plasma Lipids . . . . . . . . . . . . . . . . . . . . 201.9 Effect of Fish Oil on Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221.10 n–3 Fatty Acids and Bleeding Tendency . . . . . . . . . . . . . . . . . 241.11 Effect of n–3 Fatty Acids on Blood Pressure . . . . . . . . . . . . . . 241.12 Recommendations for Intake of n�3 Fatty Acids . . . . . . . . . . 251.13 Beneficial Effects of Olive Oil on Human Health . . . . . . . . . . 25

1.13.1 Effects of Olive Oil on Heart . . . . . . . . . . . . . . . . . . . . 251.13.2 Effects of Olive Oil on Brain . . . . . . . . . . . . . . . . . . . . 29

1.14 Harmful Effects of Trans Fatty Acids on Human Health . . . . 311.15 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

xi

2 Transport, Synthesis, and Incorporation of n–3 and n–6 Fatty Acids

in Brain Glycerophospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472.2 Transport of Dietary ARA and DHA to Brain . . . . . . . . . . . . 482.3 Importance of DHA in Neural Membranes. . . . . . . . . . . . . . . 512.4 ARA and Its Importance in Neural Membranes . . . . . . . . . . . 532.5 Biosynthesis of n–3 and n–6 Fatty Acids in Liver . . . . . . . . . . 54

2.5.1 Biosynthesis of n–3 Fatty Acids in Liver. . . . . . . . . . . . 552.5.2 Biosynthesis of n–6 Fatty Acids in Liver. . . . . . . . . . . . 58

2.6 Incorporation of Fatty Acids in Glycerophospholipids. . . . . . 602.6.1 Acyl-CoA Synthetases in Brain . . . . . . . . . . . . . . . . . . . 612.6.2 Acyl-CoA:lysophospholipid Acyltransferase

in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642.6.3 CoA-Independent Reacylation in Brain . . . . . . . . . . . . 67

2.7 Incorporation of ALA and LA in Brain Lipids . . . . . . . . . . . . 672.8 Incorporation of Docosahexaenoic Acid in Neural Membranes

in Glycerophospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682.9 Incorporation of Arachidonic Acid in Neural Membranes . . . 702.10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

3 Release of n–3 and n–6 Fatty Acids from Glycerophospholipids

in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793.2 Release of DHA from Ethanolamine or Choline

Plasmalogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803.2.1 Plasmalogen-Selective-Phospholipase A2 in Brain . . . . 813.2.2 Canine Myocardium PlsCho-PLA2. . . . . . . . . . . . . . . . 883.2.3 PlsEtn-PLA2 from Rabbit Kidney . . . . . . . . . . . . . . . . 89

3.3 Release of DHA from PtdSer. . . . . . . . . . . . . . . . . . . . . . . . . . 913.4 Receptor-Mediated Degradation of Plasmalogens . . . . . . . . . 913.5 Release of n–6 Fatty Acids from Neural Membrane

Glycerophospholipids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923.5.1 cPLA2 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923.5.2 Other Phospholipases A2. . . . . . . . . . . . . . . . . . . . . . . . 96

3.6 Regulation of PLA2 Activity in Brain . . . . . . . . . . . . . . . . . . . 963.6.1 Regulation of PlsEtn-PLA2 . . . . . . . . . . . . . . . . . . . . . . 963.6.2 Regulation of cPLA2 . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

3.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

4 Oxidation of Arachidonic and Docosahexaenoic Acids and

Neurochemical Effects of Their Metabolites on Brain . . . . . . . . . . . . 1054.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054.2 Arachidonic Acid and Its Enzymic Oxidation in Brain . . . . . . 108

xii Contents

4.2.1 Isoforms of Cyclooxygenases in Brain . . . . . . . . . . . . . 1084.2.2 Roles of Eicosanoids in Brain . . . . . . . . . . . . . . . . . . . . 1104.2.3 Isoforms of Lipoxygenases in Brain . . . . . . . . . . . . . . . 1124.2.4 Roles of Lipoxins in Brain. . . . . . . . . . . . . . . . . . . . . . . 1134.2.5 Isoforms of Cytochrome P450 Epoxygenases

in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1164.2.6 cis-Epoxyeicosatrienoic Acids . . . . . . . . . . . . . . . . . . . . 118

4.3 Non-enzymic Oxidation of Arachidonic Acid . . . . . . . . . . . . . 1194.3.1 4-Hydroxynonenal, Acrolein, and

Malondialdehyde. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194.3.2 Isoprostanes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1244.3.3 Isoketals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264.3.4 Isofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

4.4 Enzymic and Non-enzymic Oxidation of DHA. . . . . . . . . . . . 1284.4.1 Enzymic Oxidation of DHA . . . . . . . . . . . . . . . . . . . . . 1294.4.2 17S D Series Resolvins . . . . . . . . . . . . . . . . . . . . . . . . . 1304.4.3 Docosatrienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

4.5 Non-enzymic Oxidation of Docosahexaenoic Acid . . . . . . . . . 1334.5.1 4-Hydroxyhexenal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334.5.2 Neuroprostanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1344.5.3 Neuroketals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354.5.4 Neurofurans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

4.6 Enzymic Oxidation of EPA in Brain . . . . . . . . . . . . . . . . . . . . 1364.7 Non-enzymic Oxidation of EPA . . . . . . . . . . . . . . . . . . . . . . . 1384.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

5 Roles of Docosahexaenoic and Eicosapentaenoic Acids

in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515.2 Comparison of Biochemical Activities of DHA and EPA. . . . 1525.3 Role of DHA in Brain Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . 156

5.3.1 DHA-Mediated Modulation of PhysiocochemicalProperties of Membranes . . . . . . . . . . . . . . . . . . . . . . . 156

5.3.2 DHA-Mediated Modulation ofNeurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

5.3.3 DHA-Mediated Modulation of Gene Expression. . . . . 1585.3.4 DHA-Mediated Modulation of Enzymic Activities . . . 1595.3.5 DHA-Mediated Modulation of Inflammation

and Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1615.3.6 DHA-Mediated Modulation of Learning

and Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1635.3.7 DHA-Mediated Modulation of Apoptosis . . . . . . . . . . 1645.3.8 DHA and Generation of Docosanoids . . . . . . . . . . . . . 1665.3.9 DHA-Mediated Generation of Neurite Outgrowth . . . 166

Contents xiii

5.3.10 DHA-Mediated Modulation of Visual Function . . . . . 1685.3.11 DHA-Mediated Modulation of Nociception (Pain) . . . 1685.3.12 DHA, Plasma Membrane Targeting, and Raft

Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1695.4 Roles of EPA in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

5.4.1 EPA-Mediated Modulation of Inflammationand Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

5.4.2 EPA-Mediated Modulation of Depression . . . . . . . . . . 1725.4.3 EPA-Mediated Modulation of Gene Expression . . . . . 1735.4.4 EPA-Mediated Modulation of Enzymic Activities . . . . 1745.4.5 EPA and Generation of Resolvin E1. . . . . . . . . . . . . . . 1745.4.6 EPA-Mediated Modulation of Lipid Rafts. . . . . . . . . . 1765.4.7 Other Roles of EPA. . . . . . . . . . . . . . . . . . . . . . . . . . . . 176


6 Status of Docosahexaenoic Acid Levels in Aging and Consequences

of Docosahexaenoic Acid Deficiency in Normal Brain . . . . . . . . . . . . 1896.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1896.2 DHA and ARA Entry and Metabolism in Developing

Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1916.3 Alterations in DHA Levels in Various Regions

During Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936.4 DHA in Plasmalogens and Phosphatidylserine . . . . . . . . . . . . 194

6.4.1 DHA in Plasmalogens . . . . . . . . . . . . . . . . . . . . . . . . . . 1966.4.2 DHA in Phosphatidylserine . . . . . . . . . . . . . . . . . . . . . 197

6.5 Consequences of DHA Deficiency in Brain . . . . . . . . . . . . . . . 1996.5.1 Effects of DHA Deficiency on Behavioral

Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2016.5.2 Effects of DHA Deficiency on Glucose Utilization . . . . 2016.5.3 Effects of DHA Deficiency on Lipid Metabolism. . . . . 2026.5.4 Effects of DHA Deficiency on Receptor Function . . . . 2036.5.5 Effects of DHA Deficiency on Protein Function

and Enzyme Activities . . . . . . . . . . . . . . . . . . . . . . . . . . 2056.5.6 Effects of DHA Deficiency on Growth Factors . . . . . . 2066.5.7 Effects of DHA Deficiency on Ion Channels

Permeability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2076.5.8 Effects of DHA Deficiency on Blood Pressure . . . . . . . 208


7 Status and Potential Therapeutic Importance of n–3 Fatty Acids

in Neurodegenerative Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177.2 Apoptotic Cell Death in Neurodegenerative Diseases . . . . . . . 222

xiv Contents

7.3 Factors Influencing the Onset of NeurodegenerativeDiseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2237.3.1 Genetic and Environmental Factors . . . . . . . . . . . . . . . 2247.3.2 Lifestyle and Neurodegenerative Diseases . . . . . . . . . . 2257.3.3 Diet and Neurodegenerative Diseases . . . . . . . . . . . . . . 228

7.4 Importance of n–3 Fatty Acid in Diet . . . . . . . . . . . . . . . . . . . 2317.4.1 Docosahexaenoic Acid in Alzheimer

Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2327.4.2 Docosahexaenoic Acid in Parkinson

Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2387.4.3 Docosahexaenoic Acid in Amyotropic Lateral

Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2427.4.4 Docosahexaenoic Acid in Huntington Disease . . . . . . . 244

7.5 Interactions Among Excitotoxicity, Oxidative Stress, andNeuroinflammation in Neurodegenerative Diseases . . . . . . . . 244


8 Status and Potential Therapeutic Importance of n–3 Fatty

Acids in Acute Metabolic Trauma and Neurotraumatic

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2618.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2618.2 Similarities and Differences Between Ischemic and Traumatic

Neural Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2628.3 Glycerophospholipids and Fatty Acids Alterations

in Ischemic Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2668.4 Effect of n– 3 Fatty Acids on Ischemic Injury . . . . . . . . . . . . . 2708.5 Glycerophospholipids, Fatty Acid, BDNF, and cAMP

in Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2728.6 Effect of n–3 Fatty Acids on Spinal Cord Injury . . . . . . . . . . . 2748.7 Glycerophospholipid and Fatty Acids Alterations

in Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2758.8 Effect of n– 3 Fatty Acids on Traumatic Brain Injury. . . . . . . 2758.9 Glycerophospholipid and Fatty Acid Alterations

in Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2778.10 Effect of n– 3 Fatty Acids on Epilepsy. . . . . . . . . . . . . . . . . . . 2788.11 Glycerophospholipids and Fatty Acids in Kainic

Acid-Induced Neural Cell Injury . . . . . . . . . . . . . . . . . . . . . . . 2798.12 Effect of n–3 Fatty Acids in Kainic Acid-Induced

Neural Cell Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2808.13 Interactions Among Excitotoxicity, Oxidative Stress, and

Neuroinflammation Following Acute Neural Trauma . . . . . . 2818.14 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

Contents xv


in Neuropsychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2939.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2939.2 Oxidative Stress and Neuroinflammation in Neuropsychiatric

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2969.3 Dysregulation of Neurotransmission in Neuropsychiatric

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2979.4 BDNF-Mediated Signaling in Neuropsychiatric

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2999.5 Abnormalities in Essential Fatty Acid Levels

and Neuropsychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . 3039.5.1 Fatty Acids and Glycerophospholipids

in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3049.5.2 Fatty Acids and Glycerophospholipids in Depression

and Bipolar Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 3079.5.3 Fatty Acids and Glycerophospholipids in Dyslexia . . . 3099.5.4 Fatty Acids and Glycerophospholipids in Autism . . . . 310

9.6 Status of n–3 and n–6 Fatty Acids in NeuropsychiatricDisorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3119.6.1 n–6 and n–3 Fatty Acids in Depression and Bipolar

Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3119.6.2 n–6 and n–3 Fatty Acids in Aggressive Disorders and

Cocaine Addiction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3139.6.3 n–6 and n–3 Fatty Acids in Attention-Deficit/

Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . 3139.7 Effects of n–3 Fatty Acid Supplementation in Neuropsychiatric

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3159.7.1 Depression and Bipolar Disorder . . . . . . . . . . . . . . . . . 3159.7.2 Treatment with Neuropsychiatric Disorders with

High-Doses EPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3169.7.3 Treatment of ADHD with High-Doses EPA . . . . . . . . 316

9.8 Mechanism of Action of n–3 Fatty Acids in NeuropsychiatricDisorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

9.9 Involvement of Genes in Neuropsychiatric Disorders . . . . . . . 3199.10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321


in Other Neural and Non-neural Diseases . . . . . . . . . . . . . . . . . . . . . 33310.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33310.2 Effect of Fish Oil on Peroxisomes . . . . . . . . . . . . . . . . . . . . . 33310.3 Peroxisomes and Peroxisomal Disorders . . . . . . . . . . . . . . . . 334

10.3.1 Zellweger Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 33510.3.2 Adrenoleukodystrophy . . . . . . . . . . . . . . . . . . . . . . . 336

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10.4 Treatment of Peroxisomal Disorders with DHA . . . . . . . . . . 33810.4.1 DHA and Adrenomyeloneuropathy . . . . . . . . . . . . . 33910.4.2 DHA, Retinitis Pigmentosa, and Retinopathy . . . . . 339

10.5 DHA and Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34010.6 DHA and Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 34210.7 DHA and Non-neural Diseases . . . . . . . . . . . . . . . . . . . . . . . 343

10.7.1 DHA and Chronic Obstructive PulmonaryDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

10.7.2 DHA and Crohn’s Disease . . . . . . . . . . . . . . . . . . . . 34610.7.3 DHA and Systemic Lupus Erythematosus . . . . . . . . 34710.7.4 DHA and Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . 34810.7.5 DHA and Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . 35110.7.6 DHA and Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . 35410.7.7 DHA and Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . 35510.7.8 DHA and Its Clinical Trials in Chronic Diseases . . . 356

10.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358

11 Perspective and Directions for Future Development on the Effects

of Fish Oil Constituents on Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36711.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36711.2 Chronic Diseases and Dietary n–6/n–3 Ratio. . . . . . . . . . . . . 36811.3 Expression of Genes in Animals and Plants to Improve n–6

to n–3 Fatty Acids Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37111.4 Unsolved Problems of DHA and ARA Metabolism . . . . . . . 373

11.4.1 Characterization of Enzymes Associated with DHAand ARA Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 374

11.4.2 Development of Antisense Oligonucleotidesand RNAi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

11.4.3 Characterization of Receptors for Neuroprotectinsand Resolvins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

11.5 Nutrigenomics/Nutrigenetics/Transcriptomics Approachesto n–3 Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

11.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

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Abbreviations

Phosphatidylcholine PtdChoPhosphatidylethanolamine PtdEtnCholine plasmalogen PlsChoEthanolamine plasmalogen PlsEtnPhosphatidylinositol PtdInsPhoshatidylinositol 4-phosphate PtdIns4PPhosphatidylinositol 4,5-bisphosphate PtdIns(4,5)P2

Inositol-1,4,5-trisphosphate Ins-1,4,5-P3

Phosphatidic acid PtdHPhosphatidylserine PtdSerReactive oxygen species ROSNuclear factor-kappaB NF-kBArachidonic acid ARADocosahexaenoic acid DHAEicosapentaenoic acid EPALinoleic acid LAa-Linolenic acid ALAPhospholipase A2 PLA2

Phospholipase C PLCPhospholipase D PLDCyclooxygenase COXLipoxygenase LOXEpoxygenase EPOXProtein kinase C PKCProtein kinase A PKAProstaglandin PGLeukotriene LTLipoxin LXResolvin RvNeuroprotectin D NPD

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About the Author

Akhlaq A. Farooqui is a leader in the field of brain phospholipases A2, bioac-tive ether lipid metabolism, polyunsaturated fatty acid metabolism, glycero-phospholipid-, sphingolipid-, and cholesterol-derived lipid mediators, andglutamate-induced neurotoxicity. Akhlaq A. Farooqui has discovered the sti-mulation of plasmalogen-selective phospholipase A2 (PlsEtn-PLA2) and diacyl-and monoacylglycerol lipases in brains from patients with Alzheimer disease.Stimulation of PlsEtn-PLA2 produces plasmalogen deficiency and increaseslevels of eicosanoids that may be related to the loss of synapses in brains ofpatients with Alzheimer disease. Akhlaq A. Farooqui has published cuttingedge research on the generation and identification of glycerophospholipid-,sphingolipid-, and cholesterol-derived lipid mediators in kainic acid mediatedneurotoxicity by lipidomics. Akhlaq A. Farooqui has authored four mono-graphs: Glycerophospholipids in Brain: Phospholipase A2 in Neurological Dis-orders (2007); Neurochemical Aspects of Excitotoxicity (2008); Metabolism andFunctions of Bioactive Ether Lipids in Brain (2008); and Hot Topics in NeuralMembrane Lipidology (2009). All monographs are published by Springer, NewYork.

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Beneficial Effects of Fish Oil on Human Brain978-1-4419-0543-7/1.pdf · fish oil in human diet along with transport and importance of DHA in brain. Chapters 3 and 4 describe cutting-edge