Pub. Date:
Springer New York
Glycerophospholipids in the Brain: Phospholipases A2 in Neurological Disorders / Edition 1

Glycerophospholipids in the Brain: Phospholipases A2 in Neurological Disorders / Edition 1

by Akhlaq A. Farooqui, Lloyd A. Horrocks


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Glycerophospholipids in the Brain: Phospholipases A2 in Neurological Disorders / Edition 1

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 clust- ing and organizing bilayer constituents including receptors, enzymes, and i- 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 reali- tion of the very rapid turnover of these compounds and the role of choline pl- malogens (plasmenylcholine) as precursors of signaling molecules. We anticipate that this interest in research on brain phospholipids and phospholipases will c- 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.

Product Details

ISBN-13: 9780387366029
Publisher: Springer New York
Publication date: 10/18/2006
Edition description: 2007
Pages: 394
Product dimensions: 6.10(w) x 9.25(h) x 0.04(d)

Table of Contents

Phospholipid Metabolism in Brain     1
Introduction     1
Classes, occurrence, and distribution of neural glycerophospholipids     3
Biosynthesis of neural membrane glycerophospholipids     4
Incorporation of glycerophospholipids into neural membranes     8
Effect of structural variations of glycerophospholipids on neural membrane structure     10
Catabolism of neural membrane glycerophospholipids     12
Phospholipid metabolism in the nucleus     14
Roles of glycerophospholipids in brain metabolism     16
Glycerophospholipids as a storag depot for second messengers and their precursors     16
PLA[subscript 2]-generated second messengers     16
PLC-generated second messengers     18
PLD-generated second messengers     18
Involvement of PtdSer and PtdEtn in apoptosis     19
Phosphatidylinositol and membrane anchoring     21
Involvement of glycerophospholipids in regulation of enzymic activities     22
Other roles of glycerophospholipids     23
Conclusion     23
Ether Lipids in Brain     35
General considerations and importance     35
Plasmalogens     37
Biosynthesis     37
Receptor-mediated degradation     38
Roles of plasmalogens in brain tissue     42
Plasmalogens as structural components of neural membranes     43
Plasmalogens as a storage depot for second messengers     43
Plasmalogens and generation of long-chain aldehydes     44
Plasmalogens and membrane fusion     45
Plasmalogens and ion transport     45
Plasmalogen, cholesterol efflux, and atherosclerosis     46
Plasmalogens and their antioxidant activity     47
Plasmalogens in differentiation     48
Platelet-activating factor (PAF)     48
PAF biosynthesis     50
PAF degradation     51
Roles of PAF     52
Antitumor ether lipids     53
Other ether lipids     55
Conclusion     56
Phospholipases A[subscript 2] in Brain     67
Introduction     67
Multiplicity and properties of phospholipase A[subscript 2] in brain tissue     68
sPLA[subscript 2]     68
cPLA[subscript 2]     71
PlsEtn-selective PLA[subscript 2]     76
iPLA[subscript 2]     77
Platelet-activating factor acetylhydrolases (PAF-AH)     80
Other brain phospholipases A[subscript 2]     81
Brain nuclear PLA[subscript 2] activities     82
Regulation of isoforms of PLA[subscript 2] in brain tissue     83
Conclusions     85
Roles of Phospholipases A[subscript 2] in Brain     93
PLA[subscript 2] isoforms and neurotransmitter release     94
PLA[subscript 2] isoforms in long-term potentiation (LTP)     95
Involvement of PLA[subscript 2] isoforms in membrane repair     97
PLA[subscript 2] isoforms in modulation of neurite outgrowth and regeneration     98
PLA[subscript 2] isoforms in inflammatory and anti-inflammatory processes     100
Involvement of PLA[subscript 2] isoforms in the cell cycle     102
PLA[subscript 2] isoforms in tubule formation and membrane trafficking     102
PLA[subscript 2] isoforms in neurodegeneration     104
Involvement of PLA[subscript 2] isoforms in apoptosis     105
Involvement of PLA[subscript 2] isoforms in necrosis     109
Arachidonic Acid and Its Metabolites in Brain     121
Introduction     121
Incorporation of arachidonic acid and docosahexaenoic acid into neural membranes     122
Receptor-mediated release of arachidonic acid     124
Neurotrophic effects of arachidonic acid      129
Neurotoxic effects of arachidonic acid     131
Metabolism of arachidonic acid in brain     132
Importance of eicosanoids in brain     135
Docosahexaenoic Acid and Its Metabolites in Brain     147
Location and turnover of docosahexaenoic acid     147
Incorporation of docosahexaenoic acid     149
Receptor-mediated release of docosahexaenoic acid from glycerophospholipids     151
Effects of DHA and its metaboUtes on brain tissue     153
DHA in gene expression, neurotransmitter release, and enzyme regulation     154
DHA and neurite outgrowth     156
DHA and modulation of learning and memory     157
DHA and apoptotic cell death     158
DHA and generation of docosanoids     159
DHA and the immune response     160
DHA intake, oxidative stress, and other side effects     162
Nonenzymic Metabolites of Arachidonate and Docosahexaenoate in Brain     173
Introduction     173
Reactive oxygen species     173
Lipid hydroperoxides     177
Isoprostanes, isofurans, isothromboxanes, isoleukotrienes, and neuroprostanes     178
Isoprostanes     178
Isothromboxanes     182
Isofurans      183
Isoleukotrienes     184
Neuroprostanes     184
Neuroketals     184
Generation of 4-HNE and its effect on brain metabolism     185
4-HNE is a signaling molecule     185
Neurotoxic effects     186
Effects of acrolein in brain     188
Generation of DHA metabolites and their effect on brain metabolism     189
Neurotrophic effects of DHA     189
Neurotoxic effects of DHA     190
Effects of nonenzymic degradation of LA on brain metabolism     190
Lyso-Glycerophospholipids     199
Introduction     199
Effects of lyso-glycerophospholipids on neural membrane metabolism     201
1-Acyl-2-lyso-sn-GroPCho (Lyso-PtdCho)     201
Lyso-PtdEtn     206
Lyso-PdaSer     206
Lyso-PtdIns     208
Lyso-PlsEtn and lyso-PlsCho     208
Lyso-phospholipases in brain     209
Lyso-plasmalogenase in brain     211
Concluding remarks     212
Lysophosphatidic Acid and Its Metabolism in Brain     219
Functions of lysophosphatidic acid in brain     219
Synthesis and degradation of lyso-PtdH     220
LPA receptors and Lyso-PtdH-mediated signaling in brain     222
Agonists and antagonists of LPA receptors     225
Lyso-PtdH and its receptors in neurological diseases     229
Lyso-PtdH and its receptors in non-neural diseases     230
Involvement of Phospholipids and Phospholipases A[subscript 2] in Neurological Disorders     239
Introduction     239
Similarities and differences between acute neural trauma and neurodegenerative diseases     239
Involvement of excitotoxicity and glycerophospholipid degradation mediated by PLA[subscript 2] in acute neural trauma and neurodegenerative diseases     241
PLA[subscript 2] activity in neurological disorders     243
PLA[subscript 2] in ischemic injury     247
PLA[subscript 2] in Alzheimer disease     250
PLA[subscript 2] in Parkinson disease (PD) and its animal models     254
PLA[subscript 2] in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE)     255
PLA[subscript 2] in prion diseases     257
PLA[subscript 2] in spinal cord injury     258
PLA[subscript 2] in head injury     259
PLA[subscript 2] in epilepsy     259
Excitotoxicity-mediated neurodegeneration involves PLA[subscript 2] activation, generation of lipid mediators, oxidative stress and neuroinflammation      260
Inhibitors of Phospholipases A[subscript 2] and Their Use for the Treatment of Neurological Disorders     275
Introduction     275
Physiological and pharmacological effects of PLA[subscript 2] inhibitors     277
Arachidonoyl trifluoromethyl ketone (AACOCF[subscript 3])     277
Methyl arachidonoyl fluorophosphonate (MAFP)     279
Bromoenol lactone (BEL)     280
Benzenesulfonamides and alkoxybenzamidines     282
3-(Pyrrol)-2-propionic acid     282
2-Oxoamide and 1,3-disubstituted propan-2-ones     282
Choline derivatives with a long aliphatic chain as PLA[subscript 2] inhibitors     283
Pyrrolidine-based inhibitors of PLA[subscript 2]     284
Antimalarial drugs     285
Lithium and carbamazepine     286
Vitamin E and gangliosides     287
Cytidine 5-diphosphoamines (CDP-amines)     289
Long chain polyunsaturated fatty acids     289
PLA[subscript 2] antisense oligonucleotides and interfering RNA (RNAi)     290
Diffusion survival evasion peptide (DSEP)     290
sPLA[subscript 2] inhibitors     291
Annexins (lipocortins)     293
Use of PLA[subscript 2] inhibitors for the treatment of neurological disorders      294
Prevention of pain by PLA[subscript 2] inhibitors     301
Perspective and direction for future studies     302
Assay Methods for Phospholipase A[subscript 2] Activities in Brain     321
Assay methods     321
Titrimetric procedures     322
Radiochemical procedures     323
Spectrophotometric procedures     324
Use of thioester substrate analogs     324
Use of coupled enzyme assays     326
Fluorometric procedures     328
Continuous fluorometric procedures     330
Discontinuous fluorometric procedures     332
Assay of multiple forms of PLA[subscript 2] in biological samples     334
Immunological procedures     335
Glycerophospholipids and Phospholipases A[subscript 2] in Neuropsychiatric Disorders     341
Introduction     341
Schizophrenia     342
Cocaine addiction     345
Depression and bipolar disorders     346
Dyslexia     348
Autism     348
Status of n-3 and n-6 fatty acids in neuropsychiatric disorders     349
Introduction     349
Depression and bipolar disorder     349
Aggressive disorders and cocaine addiction      351
Attention-deficit hyperactivity disorder     351
Effects of n-3 fatty acid supplementation in neuropsychiatric disorders     352
Depression and bipolar disorder     352
Treatment with high-dose EPA     353
ADHD     353
Mechanism of action of n-3 fatty acids     354
Genetic involvement     355
Future Perspectives: Metabolic and Functional Aspects of Neural Membrane Glycerophospholipids     367
Index     377

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