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TitleBeneficial Effects of Fish Oil on Human Brain - A. farooqui (Springer, 2009) WW
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Table of Contents
                            Beneficial Effects of Fish Oil on Human Brain
	About the Author
Fish Oil and Importance of Its Ingredients in Human Diet
	1.1 Introduction
	1.2 n-3 Fatty Acids in Fish Oil Capsules and Krill Oil Capliques
		1.2.1 Availability of Purified Fish Oil and Krill Oil Preparations
		1.2.2 Other n-3-Enriched Manufactured Products
	1.3 Effects of Fish Oil on Human Health
	1.4 Effects of Fish Oil on Heart
		1.4.1 Antiinflammatory and Antiatherosclerotic Effects of Fish Oil
		1.4.2 Antiarrythmic Effects of Fish Oil
		1.4.3 Antithrombotic Effects of Fish Oil
		1.4.4 Effect of n-3 Fatty Acids on Revascularization
		1.4.5 n-3 or omega -3 Index and Heart Disease
	1.5 Effects of Fish Oil on Brain
		1.5.1 Effect of Fish Oil on Neural Membranes
		1.5.2 Effect of Fish Oil on Neuritogenesis
		1.5.3 Effect of n-3 Fatty Acids on Ion Channels
		1.5.4 Effect of n-3 Fatty Acids on Receptors
	1.6 Effects of Fish Oil on Lungs
	1.7 Effects of Fish Oil on Kidneys
	1.8 Effects of Fish Oil on Plasma Lipids
	1.9 Effect of Fish Oil on Liver
	1.10 n-3 Fatty Acids and Bleeding Tendency
	1.11 Effect of n-3 Fatty Acids on Blood Pressure
	1.12 Recommendations for Intake of n-3 Fatty Acids
	1.13 Beneficial Effects of Olive Oil on Human Health
		1.13.1 Effects of Olive Oil on Heart
		1.13.2 Effects of Olive Oil on Brain
	1.14 Harmful Effects of Trans Fatty Acids on Human Health
	1.15 Conclusion
Transport, Synthesis, and Incorporation of n-3 and n-6 Fatty Acids in Brain Glycerophospholipids
	2.1 Introduction
	2.2 Transport of Dietary ARA and DHA to Brain
	2.3 Importance of DHA in Neural Membranes
	2.4 ARA and Its Importance in Neural Membranes
	2.5 Biosynthesis of n-3 and n-6 Fatty Acids in Liver
		2.5.1 Biosynthesis of n-3 Fatty Acids in Liver
		2.5.2 Biosynthesis of n-6 Fatty Acids in Liver
	2.6 Incorporation of Fatty Acids in Glycerophospholipids
		2.6.1 Acyl-CoA Synthetases in Brain
		2.6.2 Acyl-CoA:lysophospholipid Acyltransferase in Brain
		2.6.3 CoA-Independent Reacylation in Brain
	2.7 Incorporation of ALA and LA in Brain Lipids
	2.8 Incorporation of Docosahexaenoic Acid in Neural Membranes in Glycerophospholipids
	2.9 Incorporation of Arachidonic Acid in Neural Membranes
	2.10 Conclusion
Release of n-3 and n-6 Fatty Acids from Glycerophospholipids in Brain
	3.1 Introduction
	3.2 Release of DHA from Ethanolamine or Choline Plasmalogen
		3.2.1 Plasmalogen-Selective-Phospholipase A2 in Brain
		3.2.2 Canine Myocardium PlsCho-PLA2
		3.2.3 PlsEtn-PLA2 from Rabbit Kidney
	3.3 Release of DHA from PtdSer
	3.4 Receptor-Mediated Degradation of Plasmalogens
	3.5 Release of n-6 Fatty Acids from Neural Membrane Glycerophospholipids
		3.5.1 cPLA2 in Brain
		3.5.2 Other Phospholipases A2
	3.6 Regulation of PLA2 Activity in Brain
		3.6.1 Regulation of PlsEtn-PLA2
		3.6.2 Regulation of cPLA2
	3.7 Conclusion
Oxidation of Arachidonic and Docosahexaenoic Acids and Neurochemical Effects of Their Metabolites on Brain
	4.1 Introduction
	4.2 Arachidonic Acid and Its Enzymic Oxidation in Brain
		4.2.1 Isoforms of Cyclooxygenases in Brain
		4.2.2 Roles of Eicosanoids in Brain
		4.2.3 Isoforms of Lipoxygenases in Brain
		4.2.4 Roles of Lipoxins in Brain
		4.2.5 Isoforms of Cytochrome P450 Epoxygenases in Brain
		4.2.6 cis-Epoxyeicosatrienoic Acids
	4.3 Non-enzymic Oxidation of Arachidonic Acid
		4.3.1 4-Hydroxynonenal, Acrolein, and Malondialdehyde
		4.3.2 Isoprostanes
		4.3.3 Isoketals
		4.3.4 Isofurans
	4.4 Enzymic and Non-enzymic Oxidation of DHA
		4.4.1 Enzymic Oxidation of DHA
		4.4.2 17S D Series Resolvins
		4.4.3 Docosatrienes
	4.5 Non-enzymic Oxidation of Docosahexaenoic Acid
		4.5.1 4-Hydroxyhexenal
		4.5.2 Neuroprostanes
		4.5.3 Neuroketals
		4.5.4 Neurofurans
	4.6 Enzymic Oxidation of EPA in Brain
	4.7 Non-enzymic Oxidation of EPA
	4.8 Conclusion
Roles of Docosahexaenoic and Eicosapentaenoic Acids in Brain
	5.1 Introduction
	5.2 Comparison of Biochemical Activities of DHA and EPA
	5.3 Role of DHA in Brain Tissue
		5.3.1 DHA-Mediated Modulation of Physiocochemical Properties of Membranes
		5.3.2 DHA-Mediated Modulation of Neurotransmission
		5.3.3 DHA-Mediated Modulation of Gene Expression
		5.3.4 DHA-Mediated Modulation of Enzymic Activities
		5.3.5 DHA-Mediated Modulation of Inflammation and Immunity
		5.3.6 DHA-Mediated Modulation of Learning and Memory
		5.3.7 DHA-Mediated Modulation of Apoptosis
		5.3.8 DHA and Generation of Docosanoids
		5.3.9 DHA-Mediated Generation of Neurite Outgrowth
		5.3.10 DHA-Mediated Modulation of Visual Function
		5.3.11 DHA-Mediated Modulation of Nociception (Pain)
		5.3.12 DHA, Plasma Membrane Targeting, and Raft Formation
	5.4 Roles of EPA in Brain
		5.4.1 EPA-Mediated Modulation of Inflammation and Immunity
		5.4.2 EPA-Mediated Modulation of Depression
		5.4.3 EPA-Mediated Modulation of Gene Expression
		5.4.4 EPA-Mediated Modulation of Enzymic Activities
		5.4.5 EPA and Generation of Resolvin E1
		5.4.6 EPA-Mediated Modulation of Lipid Rafts
		5.4.7 Other Roles of EPA
	5.5 Conclusion
Status of Docosahexaenoic Acid Levels in Aging and Consequences of Docosahexaenoic Acid Deficiency in Normal Brain
	6.1 Introduction
	6.2 DHA and ARA Entry and Metabolism in Developing Brain
	6.3 Alterations in DHA Levels in Various Regions During Aging
	6.4 DHA in Plasmalogens and Phosphatidylserine
		6.4.1 DHA in Plasmalogens
		6.4.2 DHA in Phosphatidylserine
	6.5 Consequences of DHA Deficiency in Brain
		6.5.1 Effects of DHA Deficiency on Behavioral Parameters
		6.5.2 Effects of DHA Deficiency on Glucose Utilization
		6.5.3 Effects of DHA Deficiency on Lipid Metabolism
		6.5.4 Effects of DHA Deficiency on Receptor Function
		6.5.5 Effects of DHA Deficiency on Protein Function and Enzyme Activities
		6.5.6 Effects of DHA Deficiency on Growth Factors
		6.5.7 Effects of DHA Deficiency on Ion Channels Permeability
		6.5.8 Effects of DHA Deficiency on Blood Pressure
	6.6 Conclusion
Status and Potential Therapeutic Importance of n-3 Fatty Acids in Neurodegenerative Disease
	7.1 Introduction
	7.2 Apoptotic Cell Death in Neurodegenerative Diseases
	7.3 Factors Influencing the Onset of Neurodegenerative Diseases
		7.3.1 Genetic and Environmental Factors
		7.3.2 Lifestyle and Neurodegenerative Diseases
		7.3.3 Diet and Neurodegenerative Diseases
	7.4 Importance of n-3 Fatty Acid in Diet
		7.4.1 Docosahexaenoic Acid in Alzheimer Disease
		7.4.2 Docosahexaenoic Acid in Parkinson Disease
		7.4.3 Docosahexaenoic Acid in Amyotropic Lateral Sclerosis
		7.4.4 Docosahexaenoic Acid in Huntington Disease
	7.5 Interactions Among Excitotoxicity, Oxidative Stress, and Neuroinflammation in Neurodegenerative Diseases
	7.6 Conclusion
Status and Potential Therapeutic Importance of n-3 Fatty Acids in Acute Metabolic Trauma and Neurotraumatic Disorders
	8.1 Introduction
	8.2 Similarities and Differences Between Ischemic and Traumatic Neural Injuries
	8.3 Glycerophospholipids and Fatty Acids Alterations in Ischemic Injury
	8.4 Effect of n- 3 Fatty Acids on Ischemic Injury
	8.5 Glycerophospholipids, Fatty Acid, BDNF, and cAMP in Spinal Cord Injury
	8.6 Effect of n-3 Fatty Acids on Spinal Cord Injury
	8.7 Glycerophospholipid and Fatty Acids Alterations in Traumatic Brain Injury
	8.8 Effect of n- 3 Fatty Acids on Traumatic Brain Injury
	8.9 Glycerophospholipid and Fatty Acid Alterations in Epilepsy
	8.10 Effect of n- 3 Fatty Acids on Epilepsy
	8.11 Glycerophospholipids and Fatty Acids in Kainic Acid-Induced Neural Cell Injury
	8.12 Effect of n-3 Fatty Acids in Kainic Acid-Induced Neural Cell Injury
	8.13 Interactions Among Excitotoxicity, Oxidative Stress, and Neuroinflammation Following Acute Neural Trauma
	8.14 Conclusion
Status and Potential Therapeutic Importance of n-3 Fatty Acids in Neuropsychiatric Disorders
	9.1 Introduction
	9.2 Oxidative Stress and Neuroinflammation in Neuropsychiatric Diseases
	9.3 Dysregulation of Neurotransmission in Neuropsychiatric Diseases
	9.4 BDNF-Mediated Signaling in Neuropsychiatric Disorders
	9.5 Abnormalities in Essential Fatty Acid Levels and Neuropsychiatric Disorders
		9.5.1 Fatty Acids and Glycerophospholipids in Schizophrenia
		9.5.2 Fatty Acids and Glycerophospholipids in Depression and Bipolar Disorders
		9.5.3 Fatty Acids and Glycerophospholipids in Dyslexia
		9.5.4 Fatty Acids and Glycerophospholipids in Autism
	9.6 Status of n-3 and n-6 Fatty Acids in Neuropsychiatric Disorders
		9.6.1 n-6 and n-3 Fatty Acids in Depression and Bipolar Disorder
		9.6.2 n-6 and n-3 Fatty Acids in Aggressive Disorders and Cocaine Addiction
		9.6.3 n-6 and n-3 Fatty Acids in Attention-Deficit/Hyperactivity Disorder
	9.7 Effects of n-3 Fatty Acid Supplementation in Neuropsychiatric Disorders
		9.7.1 Depression and Bipolar Disorder
		9.7.2 Treatment with Neuropsychiatric Disorders with High-Doses EPA
		9.7.3 Treatment of ADHD with High-Doses EPA
	9.8 Mechanism of Action of n-3 Fatty Acids in Neuropsychiatric Disorders
	9.9 Involvement of Genes in Neuropsychiatric Disorders
	9.10 Conclusion
Status and Potential Therapeutic Importance of n-3 Fatty Acids in Other Neural and Non-neural Diseases
	10.1 Introduction
	10.2 Effect of Fish Oil on Peroxisomes
	10.3 Peroxisomes and Peroxisomal Disorders
		10.3.1 Zellweger Syndrome
		10.3.2 Adrenoleukodystrophy
	10.4 Treatment of Peroxisomal Disorders with DHA
		10.4.1 DHA and Adrenomyeloneuropathy
		10.4.2 DHA, Retinitis Pigmentosa, and Retinopathy
	10.5 DHA and Prion Diseases
	10.6 DHA and Multiple Sclerosis
	10.7 DHA and Non-neural Diseases
		10.7.1 DHA and Chronic Obstructive Pulmonary Disease
		10.7.2 DHA and Crohn’s Disease
		10.7.3 DHA and Systemic Lupus Erythematosus
		10.7.4 DHA and Cystic Fibrosis
		10.7.5 DHA and Arthritis
		10.7.6 DHA and Osteoporosis
		10.7.7 DHA and Psoriasis
		10.7.8 DHA and Its Clinical Trials in Chronic Diseases
	10.8 Conclusion
Perspective and Directions for Future Development on the Effects of Fish Oil Constituents on Brain
	11.1 Introduction
	11.2 Chronic Diseases and Dietary n-6/n-3 Ratio
	11.3 Expression of Genes in Animals and Plants to Improve n-6 to n-3 Fatty Acids Ratio
	11.4 Unsolved Problems of DHA and ARA Metabolism
		11.4.1 Characterization of Enzymes Associated with DHA and ARA Metabolism
		11.4.2 Development of Antisense Oligonucleotides and RNAi
		11.4.3 Characterization of Receptors for Neuroprotectins and Resolvins
	11.5 Nutrigenomics/Nutrigenetics/Transcriptomics Approaches to n-3 Fatty Acids
	11.6 Conclusion
Document Text Contents
Page 204

stability and functions of myelin and plasmamembranes. Large amounts of DHA

accumulate in the brain gray matter and in visual elements of the retina during the

development. Deficiency of essential fatty acids in neonatal period not only delays

myelinogenesis, producing impairment in learning andmemory,motor, vision, and

auditory abnormalities, but also decreases membrane fluidity and affects activities

of membrane-bound enzymes and ion channels (Table 6.1) (Salvati et al., 2000;

Stockard et al., 2000). Studies on the effect of low- and high-DHA diet in senes-

cence-accelerated prone 8 (SAMP8) mice indicate that after 8 weeks of feeding

DHA-enriched diet, SAMP8mice show improvement in acquisition and retention

in a T-maze foot shock avoidance test and a higher proportion of DHA in

hippocampal and amygdala glycerophospholipids (Petursdottir et al., 2008), sug-

gesting that, in mature animals, DHA is incorporated into brain glycerophospho-

lipids and that dietary DHA may be associated with delay in cognitive decline

(Petursdottir et al., 2008).
Autopsy and neuroimaging studies have indicated that during aging process

changes in white matter are more prominent than cortical changes, at least

during certain segments of the age span and in certain regions of the brain

(Knight, 2000). Aging produces changes in glycerophospholipid–fatty acid

composition, but no significant changes in the content of different glyceropho-

spholipid classes have been observed, except for sphingomyelin, phosphatidic

acid, plasmalogens, and cardiolipin (Horrocks et al., 1981; Giusto et al., 1992,

2002; Farooqui and Farooqui, 2009). An increase in microglial activation has

also been reported in several brain regions, including hippocampus, during

aging (Finch and Cohen, 1997). Possible mechanisms may include microglial

reaction to increased production of lipid mediators, oxidation of oxidized

Table 6.1 Effect of DHA deficiency on glucose uptake, neurotransmitter release, and neuron
size in brain

Neurotransmitter Brain region Effect References


Hippocampus Decreased Kuperstein et al. (2008)

Cholinergic Frontal cortex and

Decreased Aids et al. (2003)

Serotonin Hippocampus Increased Kodas et al. (2004)

Glutamatergic Hippocampus and

Decreased Dyall et al. (2007)


Kuperstein et al.

Increased Berry et al. (2005)

Glucose uptake Kuperstein et al.

Decreased Ximenes da Silva et al. (2002);
Pifferi et al. (2007)


Olfactory bulb and

Decreased Hichami et al. (2007)


Neural membranes Increased Hashimoto et al. (2006)

Neuron body size Hippocampus Decreased Ahmad et al. (2002a,b)

190 6 Status of Docosahexaenoic Acid Levels in Aging

Page 408

Nutrigenetics, 376–378
Nutrigenomics, 376–378
Nutrigenomics, 376


Oleic acid, see Olive oil
Olive oil

beneficial effects, 25
on brain, 29–31
on heart, 25–29

See also Fish oil; n–3 fatty acids
Osteoarthritis, 352
Osteoporosis, 354–355
Oxidation, 105

ARA, 108–118
DHA, 129–133
EPA, 136–138

ARA, 119–128
DHA, 133–136
EPA, 138–139

Oxidative stress
in neuropsychiatric disorders, 296–297
interactions with excitotoxicity and

neuroinflammation in
neurodegenerative diseases,

neurotraumatic disorders, 281–283

neurodegenerative diseases and,


Pain, see Nociception (pain)
Parkinson disease (PD)

DHA importance in diet and, 238–242
genetic and environmental factors, 224
interactions among excitotoxicity,

oxidative stress, and
neuroinflammation in, 247

See also Neurodegenerative diseases
Peroxisomal disorders

adrenoleukodystrophy (ALD), 336–338
contiguous gene syndrome, 334–335
DHA for treating, 338–339

adrenomyeloneuropathy, 339
retinitis pigmentosa (RP), 339–341
retinopathy, 340–341

fish oil effect on peroxisomes and,

peroxisomal enzyme deficiencies,

peroxisome biogenesis disorders (PBDs),

peroxisomes and, 334–338
Zellweger syndrome, 335–336
See also Multiple sclerosis (MS); Prion

Phosphatidylserine (PtdSer)

brain aging and DHA in, 194–199
DHA release from, 91
See also Plasmalogens

Phospholipase A2 (PLA2)
cytosolic (cPLA2), 92–98
in rat brain, 96

PlsCho-PLA2, 88–89
PlsEtn-PLA2, 81–92, 96–97

Plasma lipids
fish oil effects on

LDL, 20–22
VLDL, 20–22

See also Brain glycerophospholipids
Plasma membrane

DHA role in targeting of, 169
See also Neural membranes

brain aging and DHA in, 194–196
DHA release from

choline plasmalogen (PlsCho-PLA2 in
canine myocardium), 88–89

ethanolamine plasmalogen
(PlsEtn-PLA2 in bovine brain),

ethanolamine plasmalogen
(PlsEtn-PLA2 in rabbit kidney),

receptor-mediated degradation of
plasmalogens, 91–92

PlsEtn-PLA2 regulation, 96–97
See also Phosphatidylserine (PtdSer);

Phospholipase A2 (PLA2)
Prion diseases

DHA and, 340–342
EPA and, 341
See also Multiple sclerosis (MS);

Peroxisomal disorders
Protein function

DHA deficiency in brain and, 203–205
See also n–3 fatty acids

DHA and, 355–356
psoriatic arthritis, 352

Index 395

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