Advertisement

Docosahexaenoic acid (DHA): An essential nutrient and a nutraceutical for brain health and diseases

      Highlights

      • Multi-function roles of DHA in maintaining brain health throughout the life span.
      • DHA undergoes enzymatic and non-enzymatic conversions to form oxilipins.
      • 4-Hydroxyhexenal (4-HHE) regulates cell redox homeostasis through Nrf2/ARE.
      • DHA derived lipid mediators are neuroprotective and ameliorate neurological disorders.

      Abstract

      Docosahexaenoic acid (DHA), a polyunsaturated fatty acid (PUFA) enriched in phospholipids in the brain and retina, is known to play multi-functional roles in brain health and diseases. While arachidonic acid (AA) is released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2), DHA is linked to action of the Ca2+-independent iPLA2. DHA undergoes enzymatic conversion by 15-lipoxygenase (Alox 15) to form oxylipins including resolvins and neuroprotectins, which are powerful lipid mediators. DHA can also undergo non-enzymatic conversion by reacting with oxygen free radicals (ROS), which cause the production of 4-hydoxyhexenal (4-HHE), an aldehyde derivative which can form adducts with DNA, proteins and lipids. In studies with both animal models and humans, there is evidence that inadequate intake of maternal n-3 PUFA may lead to aberrant development and function of the central nervous system (CNS). What is less certain is whether consumption of n-3 PUFA is important in maintaining brain health throughout one's life span. Evidence mostly from non-human studies suggests that DHA intake above normal nutritional requirements might modify the risk/course of a number of diseases of the brain. This concept has fueled much of the present interest in DHA research, in particular, in attempts to delineate mechanisms whereby DHA may serve as a nutraceutical and confer neuroprotective effects. Current studies have revealed ability for the oxylipins to regulation of cell redox homeostasis through the Nuclear factor (erythroid-derived 2)-like 2/Antioxidant response element (Nrf2/ARE) anti-oxidant pathway, and impact signaling pathways associated with neurotransmitters, and modulation of neuronal functions involving brain-derived neurotropic factor (BDNF). This review is aimed at describing recent studies elaborating these mechanisms with special regard to aging and Alzheimer's disease, autism spectrum disorder, schizophrenia, traumatic brain injury, and stroke.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kim H.Y.
        • Huang B.X.
        • Spector A.A.
        Phosphatidylserine in the brain: metabolism and function.
        Prog. Lipid Res. 2014; 56: 1-18
        • Sun G.Y.
        • Horrocks L.A.
        The fatty acid and aldehyde composition of the major phospholipids of mouse brain.
        Lipids. 1968; 3: 79-83
        • Sun G.Y.
        • Horrocks L.A.
        The acyl and alk-1-enyl groups of the major phosphoglycerides from ox brain myelin and mouse brain microsomal, mitochondrial and myelin fractions.
        Lipids. 1970; 5: 1006-1012
        • Segawa K.
        • Kurata S.
        • Yanagihashi Y.
        • Brummelkamp T.R.
        • Matsuda F.
        • Nagata S.
        Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure.
        Science. 2014; 344: 1164-1168
        • Chen C.T.
        • Green J.T.
        • Orr S.K.
        • Bazinet R.P.
        Regulation of brain polyunsaturated fatty acid uptake and turnover.
        Prostaglandins Leukot. Ess. Fat. Acids. 2008; 79: 85-91
        • Premkumar N.
        • Sun G.Y.
        • MacQuarrie R.A.
        Acylation of lysophosphatidylcholine by brain membranes.
        J. Neurosci. Res. 1993; 35: 321-326
        • Bazan N.G.
        • Aveldano M.I.
        • de Caldironi
        • Rodriguez E.B.
        de Turco, Rapid release of free arachidonic acid in the central nervous system due to stimulation.
        Prog. Lipid Res. 1981; 20: 523-529
        • Leslie C.C.
        Cytosolic phospholipase A(2): physiological function and role in disease.
        J. Lipid Res. 2015; 56: 1386-1402
        • Ramanadham S.
        • Ali T.
        • Ashley J.W.
        • Bone R.N.
        • Hancock W.D.
        • Lei X.
        Calcium-independent phospholipases A2 and their roles in biological processes and diseases.
        J. Lipid Res. 2015; 56: 1643-1668
        • Sun G.Y.
        • Chuang D.Y.
        • Zong Y.
        • Jiang J.
        • Lee J.C.
        • Gu Z.
        • Simonyi A.
        Role of cytosolic phospholipase A2 in oxidative and inflammatory signaling pathways in different cell types in the central nervous system.
        Mol. Neurobiol. 2014; 50: 6-14
        • Chuang D.Y.
        • Simonyi A.
        • Kotzbauer P.T.
        • Gu Z.
        • Sun G.Y.
        Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway.
        J. Neuroinflamm. 2015; 12: 199
        • Green J.T.
        • Orr S.K.
        • Bazinet R.P.
        The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids.
        J. Lipid Res. 2008; 49: 939-944
        • Strokin M.
        • Sergeeva M.
        • Reiser G.
        Prostaglandin synthesis in rat brain astrocytes is under the control of the n-3 docosahexaenoic acid, released by group VIB calcium-independent phospholipase A2.
        J. Neurochem. 2007; 102: 1771-1782
        • Rao J.S.
        • Ertley R.N.
        • DeMar Jr., J.C.
        • Rapoport S.I.
        • Bazinet R.P.
        • Lee H.J.
        Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex.
        Mol. Psychiatry. 2007; 12: 151-157
        • Nordmann C.
        • Strokin M.
        • Schonfeld P.
        • Reiser G.
        Putative roles of Ca(2+) -independent phospholipase A2 in respiratory chain-associated ROS production in brain mitochondria: influence of docosahexaenoic acid and bromoenol lactone.
        J. Neurochem. 2014; 131: 163-176
        • Schaeffer E.L.
        • Gattaz W.F.
        Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory.
        Psychopharmacology. 2005; 181: 392-400
        • Shalini S.M.
        • Chew W.S.
        • Rajkumar R.
        • Dawe G.S.
        • Ong W.Y.
        Role of constitutive calcium-independent phospholipase A2 beta in hippocampo-prefrontal cortical long term potentiation and spatial working memory.
        Neurochem. Int. 2014; 78: 96-104
        • Chew W.S.
        • Ong W.Y.
        Regulation of calcium-independent phospholipase A2 expression by adrenoceptors and sterol regulatory element binding protein-potential crosstalk between sterol and glycerophospholipid mediators.
        Mol. Neurobiol. 2016; 53: 500-517
        • Chew W.S.
        • Shalini S.M.
        • Torta F.
        • Wenk M.R.
        • Stohler C.
        • Yeo J.F.
        • Herr D.R.
        • Ong W.Y.
        Role of prefrontal cortical calcium-independent phospholipase A2 in antinociceptive effect of the norepinephrine reuptake inhibitor antidepresssant maprotiline.
        Neuroscience. 2017; 340: 91-100
        • Lee L.H.
        • Tan C.H.
        • Shui G.
        • Wenk M.R.
        • Ong W.Y.
        Role of prefrontal cortical calcium independent phospholipase A(2) in antidepressant-like effect of maprotiline.
        Int. J. Neuropsychopharmacol. 2012; 15: 1087-1098
        • Shalini S.M.
        • Ho C.F.
        • Ng Y.K.
        • Tong J.X.
        • Ong E.S.
        • Herr D.R.
        • Dawe G.S.
        • Ong W.Y.
        Distribution of Alox15 in the rat brain and its role in prefrontal cortical resolvin D1 formation and spatial working memory.
        Mol. Neurobiol. 2017;
        • Weiser M.J.
        • Butt C.M.
        • Mohajeri M.H.
        Docosahexaenoic acid and cognition throughout the lifespan.
        Nutrients. 2016; 8: 99
        • Liu J.J.
        • Green P.
        • John Mann J.
        • Rapoport S.I.
        • Sublette M.E.
        Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease.
        Brain Res. 2015; 1597: 220-246
        • Yavin E.
        • Glozman S.
        • Green P.
        Docosahexaenoic acid accumulation in the prenatal brain: prooxidant and antioxidant features.
        J. Mol. Neurosci. 2001; 16 (discussion 279-284): 229-235
        • Norris S.E.
        • Friedrich M.G.
        • Mitchell T.W.
        • Truscott R.J.
        • Else P.L.
        Human prefrontal cortex phospholipids containing docosahexaenoic acid increase during normal adult aging, whereas those containing arachidonic acid decrease.
        Neurobiol. Aging. 2015; 36: 1659-1669
        • Gharami K.
        • Das M.
        • Das S.
        Essential role of docosahexaenoic acid towards development of a smarter brain.
        Neurochem. Int. 2015; 89: 51-62
        • Luchtman D.W.
        • Song C.
        Cognitive enhancement by omega-3 fatty acids from child-hood to old age: findings from animal and clinical studies.
        Neuropharmacology. 2013; 64: 550-565
        • Spector A.A.
        Essentiality of fatty acids.
        Lipids. 1999; 34: S1-S3
        • Guesnet P.
        • Alessandri J.M.
        Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) - Implications for dietary recommendations.
        Biochimie. 2011; 93: 7-12
        • Neuringer M.
        • Anderson G.J.
        • Connor W.E.
        The essentiality of n-3 fatty acids for the development and function of the retina and brain.
        Annu. Rev. Nutr. 1988; 8: 517-541
        • Cunnane S.C.
        Problems with essential fatty acids: time for a new paradigm?.
        Prog. Lipid Res. 2003; 42: 544-568
        • Dyall S.C.
        Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.
        Front. Aging Neurosci. 2015; 7: 52
        • Dyall S.C.
        • Michael-Titus A.T.
        Neurological benefits of omega-3 fatty acids.
        Neuromolecular Med. 2008; 10: 219-235
        • Trepanier M.O.
        • Hopperton K.E.
        • Orr S.K.
        • Bazinet R.P.
        N-3 polyunsaturated fatty acids in animal models with neuroinflammation: an update.
        Eur. J. Pharmacol. 2016; 785: 187-206
        • Pan J.P.
        • Zhang H.Q.
        • Wei W.
        • Guo Y.F.
        • Na X.
        • Cao X.H.
        • Liu L.J.
        Some subtypes of endocannabinoid/endovanilloid receptors mediate docosahexaenoic acid-induced enhanced spatial memory in rats.
        Brain Res. 2011; 1412: 18-27
        • Davis-Bruno K.
        • Tassinari M.S.
        Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature.
        Birth Defects Res. B Dev. Reprod. Toxicol. 2011; 92: 240-250
        • Denis I.
        • Potier B.
        • Vancassel S.
        • Heberden C.
        • Lavialle M.
        Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms.
        Ageing Res. Rev. 2013; 12: 579-594
        • Afshordel S.
        • Hagl S.
        • Werner D.
        • Rohner N.
        • Kogel D.
        • Bazan N.G.
        • Eckert G.P.
        Omega-3 polyunsaturated fatty acids improve mitochondrial dysfunction in brain aging--Impact of Bcl-2 and NPD-1 like metabolites.
        Prostaglandins Leukot. Ess. Fat. Acids. 2015; 92: 23-31
        • Jiang L.H.
        • Shi Y.
        • Wang L.S.
        • Yang Z.R.
        The influence of orally administered docosahexaenoic acid on cognitive ability in aged mice.
        J. Nutr. Biochem. 2009; 20: 735-741
        • Labrousse V.F.
        • Nadjar A.
        • Joffre C.
        • Costes L.
        • Aubert A.
        • Gregoire S.
        • Bretillon L.
        • Laye S.
        Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.
        PLoS One. 2012; 7: e36861
        • Petursdottir A.L.
        • Farr S.A.
        • Morley J.E.
        • Banks W.A.
        • Skuladottir G.V.
        Effect of dietary n-3 polyunsaturated fatty acids on brain lipid fatty acid composition, learning ability, and memory of senescence-accelerated mouse.
        J. Gerontol. A Biol. Sci. Med. Sci. 2008; 63: 1153-1160
        • Hooijmans C.R.
        • Van C.E.
        • der Zee
        • Dederen P.J.
        • Brouwer K.M.
        • Reijmer Y.D.
        • van Groen T.
        • Broersen L.M.
        • Lutjohann D.
        • Heerschap A.
        • Kiliaan A.J.
        DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice.
        Neurobiol. Dis. 2009; 33: 482-498
        • Fiol-deRoque M.A.
        • Gutierrez-Lanza R.
        • Teres S.
        • Torres M.
        • Barcelo P.
        • Rial R.V.
        • Verkhratsky A.
        • Escriba P.V.
        • Busquets X.
        • Rodriguez J.J.
        Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer's disease following 2-hydroxy-DHA treatment.
        Biogerontology. 2013; 14: 763-775
        • Arsenault D.
        • Julien C.
        • Tremblay C.
        • Calon F.
        DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice.
        PLoS One. 2011; 6: e17397
        • Hosono T.
        • Mouri A.
        • Nishitsuji K.
        • Jung C.G.
        • Kontani M.
        • Tokuda H.
        • Kawashima H.
        • Shibata H.
        • Suzuki T.
        • Nabehsima T.
        • Michikawa M.
        Arachidonic or docosahexaenoic acid diet prevents memory impairment in Tg2576 mice.
        J. Alzheimers Dis. 2015; 48: 149-162
        • Parrott M.D.
        • Winocur G.
        • Bazinet R.P.
        • Ma D.W.
        • Greenwood C.E.
        Whole-food diet worsened cognitive dysfunction in an Alzheimer's disease mouse model.
        Neurobiol. Aging. 2015; 36: 90-99
        • Calon F.
        • Lim G.P.
        • Yang F.
        • Morihara T.
        • Teter B.
        • Ubeda O.
        • Rostaing P.
        • Triller A.
        • Salem Jr., N.
        • Ashe K.H.
        • Frautschy S.A.
        • Cole G.M.
        Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.
        Neuron. 2004; 43: 633-645
        • Green K.N.
        • Martinez-Coria H.
        • Khashwji H.
        • Hall E.B.
        • Yurko-Mauro K.A.
        • Ellis L.
        • LaFerla F.M.
        Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels.
        J. Neurosci. 2007; 27: 4385-4395
        • Hooijmans C.R.
        • Graven C.
        • Dederen P.J.
        • Tanila H.
        • van Groen T.
        • Kiliaan A.J.
        Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice.
        Brain Res. 2007; 1181: 93-103
        • Oksman M.
        • Iivonen H.
        • Hogyes E.
        • Amtul Z.
        • Penke B.
        • Leenders I.
        • Broersen L.
        • Lutjohann D.
        • Hartmann T.
        • Tanila H.
        Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice.
        Neurobiol. Dis. 2006; 23: 563-572
        • Torres M.
        • Price S.L.
        • Fiol-Deroque M.A.
        • Marcilla-Etxenike A.
        • Ahyayauch H.
        • Barcelo-Coblijn G.
        • Teres S.
        • Katsouri L.
        • Ordinas M.
        • Lopez D.J.
        • Ibarguren M.
        • Goni F.M.
        • Busquets X.
        • Vitorica J.
        • Sastre M.
        • Escriba P.V.
        Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease.
        Biochim. Biophys. Acta. 2014; 1838: 1680-1692
        • Lim G.P.
        • Calon F.
        • Morihara T.
        • Yang F.
        • Teter B.
        • Ubeda O.
        • Salem Jr., N.
        • Frautschy S.A.
        • Cole G.M.
        A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.
        J. Neurosci. 2005; 25: 3032-3040
        • Perez S.E.
        • Berg B.M.
        • Moore K.A.
        • He B.
        • Counts S.E.
        • Fritz J.J.
        • Hu Y.S.
        • Lazarov O.
        • Lah J.J.
        • Mufson E.J.
        DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects.
        J. Neurosci. Res. 2010; 88: 1026-1040
        • Devassy J.G.
        • Leng S.
        • Gabbs M.
        • Monirujjaman M.
        • Aukema H.M.
        Omega-3 polyunsaturated fatty acids and oxylipins in neuroinflammation and management of alzheimer disease.
        Adv. Nutr. 2016; 7: 905-916
        • Schaeffer E.L.
        • Forlenza O.V.
        • Gattaz W.F.
        Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.
        Psychopharmacology. 2009; 202: 37-51
        • Mazzocchi-Jones D.
        Impaired corticostriatal LTP and depotentiation following iPLA2 inhibition is restored following acute application of DHA.
        Brain Res. Bull. 2015; 111: 69-75
        • Shelat P.B.
        • Chalimoniuk M.
        • Wang J.H.
        • Strosznajder J.B.
        • Lee J.C.
        • Sun A.Y.
        • Simonyi A.
        • Sun G.Y.
        Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons.
        J. Neurochem. 2008; 106: 45-55
        • He Y.
        • Cui J.
        • Lee J.C.
        • Ding S.
        • Chalimoniuk M.
        • Simonyi A.
        • Sun A.Y.
        • Gu Z.
        • Weisman G.A.
        • Wood W.G.
        • Sun G.Y.
        Prolonged exposure of cortical neurons to oligomeric amyloid-beta impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.
        ASN Neuro. 2011; 3: e00050
        • Osborne C.
        • West E.
        • Nolan W.
        • McHale-Owen H.
        • Williams A.
        • Bate C.
        Glimepiride protects neurons against amyloid-beta-induced synapse damage.
        Neuropharmacology. 2016; 101: 225-236
        • Zhu D.
        • Lai Y.
        • Shelat P.B.
        • Hu C.
        • Sun G.Y.
        • Lee J.C.
        Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction.
        J. Neurosci. 2006; 26: 11111-11119
        • Heras-Sandoval D.
        • Pedraza-Chaverri J.
        • Perez-Rojas J.M.
        Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer's disease.
        J. Neuroinflamm. 2016; 13: 61
        • Hjorth E.
        • Zhu M.
        • Toro V.C.
        • Vedin I.
        • Palmblad J.
        • Cederholm T.
        • Freund-Levi Y.
        • Faxen-Irving G.
        • Wahlund L.O.
        • Basun H.
        • Eriksdotter M.
        • Schultzberg M.
        Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-beta42 by human microglia and decrease inflammatory markers.
        J. Alzheimers Dis. 2013; 35: 697-713
        • Morris M.C.
        • Evans D.A.
        • Tangney C.C.
        • Bienias J.L.
        • Wilson R.S.
        Fish consumption and cognitive decline with age in a large community study.
        Arch. Neurol. 2005; 62: 1849-1853
        • Serini S.
        • Calviello G.
        Reduction of oxidative/nitrosative stress in brain and its involvement in the neuroprotective effect of n-3 PUFA in alzheimer's disease.
        Curr. Alzheimer Res. 2016; 13: 123-134
        • Zhang Y.
        • Chen J.
        • Qiu J.
        • Li Y.
        • Wang J.
        • Jiao J.
        Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies.
        Am. J. Clin. Nutr. 2016; 103: 330-340
        • Burckhardt M.
        • Herke M.
        • Wustmann T.
        • Watzke S.
        • Langer G.
        • Fink A.
        Omega-3 fatty acids for the treatment of dementia.
        Cochrane Database Syst. Rev. 2016; 4 (CD009002)
        • Yanai H.
        Effects of N-3 Polyunsaturated Fatty Acids on Dementia.
        J. Clin. Med. Res. 2017; 9: 1-9
        • Freund-Levi Y.
        • Eriksdotter-Jonhagen M.
        • Cederholm T.
        • Basun H.
        • Faxen-Irving G.
        • Garlind A.
        • Vedin I.
        • Vessby B.
        • Wahlund L.O.
        • Palmblad J.
        Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: omegad study: a randomized double-blind trial.
        Arch. Neurol. 2006; 63: 1402-1408
        • Chew E.Y.
        • Clemons T.E.
        • Agron E.
        • Launer L.J.
        • Grodstein F.
        • Bernstein P.S.
        G. age-related eye disease study 2 Research, Effect of omega-3 fatty acids, lutein/Zeaxanthin, or Other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial.
        JAMA. 2015; 314: 791-801
        • de Souza Fernandes D.P.
        • Canaan Rezende F.A.
        • Pereira Rocha G.
        • De Santis Filgueiras M.
        • Silva Moreira P.R.
        • Goncalves Alfenas Rde C.
        Effect of eicosapentaenoic acid and docosahexaenoic acid Supplementations to control cognitive decline in dementia and Alzheimer's disease: a systematic review.
        Nutr. Hosp. 2015; 32: 528-533
        • van de Rest O.
        • Wang Y.
        • Barnes L.L.
        • Tangney C.
        • Bennett D.A.
        • Morris M.C.
        APOE epsilon4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline.
        Neurology. 2016; 86: 2063-2070
        • Kariv-Inbal Z.
        • Yacobson S.
        • Berkecz R.
        • Peter M.
        • Janaky T.
        • Lutjohann D.
        • Broersen L.M.
        • Hartmann T.
        • Michaelson D.M.
        The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol.
        J. Alzheimers Dis. 2012; 28: 667-683
        • Vandal M.
        • Alata W.
        • Tremblay C.
        • Rioux-Perreault C.
        • Salem Jr., N.
        • Calon F.
        • Plourde M.
        Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.
        J. Neurochem. 2014; 129: 516-526
        • Cederholm T.
        Fish consumption and omega-3 fatty acid supplementation for prevention or treatment of cognitive decline, dementia or Alzheimer's disease in older adults - any news?.
        Curr. Opin. Clin. Nutr. Metab. Care. 2017; 20: 104-109
        • Al-Farsi Y.M.
        • Waly M.I.
        • Deth R.C.
        • Al-Sharbati M.M.
        • Al-Shafaee M.
        • Al-Farsi O.
        • Al-Khaduri M.M.
        • Al-Adawi S.
        • Hodgson N.W.
        • Gupta I.
        • Ouhtit A.
        Impact of nutrition on serum levels of docosahexaenoic acid among Omani children with autism.
        Nutrition. 2013; 29: 1142-1146
        • El-Ansary A.K.
        • Bacha A.G.
        • Al-Ayahdi L.Y.
        Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia.
        Lipids Health Dis. 2011; 10: 63
        • Mostafa G.A.
        • Al-Ayadhi L.Y.
        Reduced levels of plasma polyunsaturated fatty acids and serum carnitine in autistic children: relation to gastrointestinal manifestations.
        Behav. Brain Funct. 2015; 11: 4
        • Sliwinski S.
        • Croonenberghs J.
        • Christophe A.
        • Deboutte D.
        • Maes M.
        Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism?.
        Neuro Endocrinol. Lett. 2006; 27: 465-471
        • Vancassel S.
        • Durand G.
        • Barthelemy C.
        • Lejeune B.
        • Martineau J.
        • Guilloteau D.
        • Andres C.
        • Chalon S.
        Plasma fatty acid levels in autistic children.
        Prostaglandins Leukot. Ess. Fat. Acids. 2001; 65: 1-7
        • Ooi Y.P.
        • Weng S.J.
        • Kossowsky J.
        • Gerger H.
        • Sung M.
        Oxytocin and autism spectrum disorders: a systematic review and meta-analysis of randomized controlled trials.
        Pharmacopsychiatry. 2017; 50: 5-13
        • Posar A.
        • Visconti P.
        Omega-3 supplementation in autism spectrum disorders: a still open question?.
        J. Pediatr. Neurosci. 2016; 11: 225-227
        • Mankad D.
        • Dupuis A.
        • Smile S.
        • Roberts W.
        • Brian J.
        • Lui T.
        • Genore L.
        • Zaghloul D.
        • Iaboni A.
        • Marcon P.M.
        • Anagnostou E.
        A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism.
        Mol. Autism. 2015; 6: 18
        • Horvath A.
        • Lukasik J.
        • Szajewska H.
        omega-3 fatty acid supplementation does not affect autism spectrum disorder in children: a systematic review and meta-analysis.
        J. Nutr. 2017;
        • James S.
        • Montgomery P.
        • Williams K.
        Omega-3 fatty acids supplementation for autism spectrum disorders (ASD).
        Cochrane Database Syst. Rev. 2011; (CD007992)
        • Julvez J.
        • Mendez M.
        • Fernandez-Barres S.
        • Romaguera D.
        • Vioque J.
        • Llop S.
        • Ibarluzea J.
        • Guxens M.
        • Avella-Garcia C.
        • Tardon A.
        • Riano I.
        • Andiarena A.
        • Robinson O.
        • Arija V.
        • Esnaola M.
        • Ballester F.
        • Sunyer J.
        Maternal consumption of seafood in pregnancy and child neuropsychological development: a longitudinal study based on a population with high consumption levels.
        Am. J. Epidemiol. 2016; 183: 169-182
        • Lyall K.
        • Munger K.L.
        • O'Reilly E.J.
        • Santangelo S.L.
        • Ascherio A.
        Maternal dietary fat intake in association with autism spectrum disorders.
        Am. J. Epidemiol. 2013; 178: 209-220
        • Tang M.
        • Zhang M.
        • Cai H.
        • Li H.
        • Jiang P.
        • Dang R.
        • Liu Y.
        • He X.
        • Xue Y.
        • Cao L.
        • Wu Y.
        Maternal diet of polyunsaturated fatty acid altered the cell proliferation in the dentate gyrus of hippocampus and influenced glutamatergic and serotoninergic systems of neonatal female rats.
        Lipids Health Dis. 2016; 15: 71
        • Pietropaolo S.
        • Goubran M.G.
        • Joffre C.
        • Aubert A.
        • Lemaire-Mayo V.
        • Crusio W.E.
        • Laye S.
        Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice.
        Psychoneuroendocrinology. 2014; 49: 119-129
        • Matsui Y.K.
        • Hecht F.
        • Fritsche P.
        • Will K.
        • Beversdorf M.
        • Docosahexaenoic D.
        acid (DHA) rescued autistic symptoms accompanied by dopaminergic change on a gene/prenatal stress mouse model.
        Soc. Neurosci. Abstr. 2015; : 26
        • Weiser M.J.
        • Mucha B.
        • Denheyer H.
        • Atkinson D.
        • Schanz N.
        • Vassiliou E.
        • Benno R.H.
        Dietary docosahexaenoic acid alleviates autistic-like behaviors resulting from maternal immune activation in mice.
        Prostaglandins Leukot. Ess. Fat. Acids. 2016; 106: 27-37
        • Gao J.
        • Wang X.
        • Sun H.
        • Cao Y.
        • Liang S.
        • Wang H.
        • Wang Y.
        • Yang F.
        • Zhang F.
        • Wu L.
        Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model.
        Int. J. Dev. Neurosci. 2016; 49: 67-78
        • Jones K.L.
        • Will M.J.
        • Hecht P.M.
        • Parker C.L.
        • Beversdorf D.Q.
        Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring.
        Behav. Brain Res. 2013; 238: 193-199
        • Meyza K.Z.
        • Defensor E.B.
        • Jensen A.L.
        • Corley M.J.
        • Pearson B.L.
        • Pobbe R.L.
        • Bolivar V.J.
        • Blanchard D.C.
        • Blanchard R.J.
        The BTBR T+ tf/J mouse model for autism spectrum disorders-in search of biomarkers.
        Behav. Brain Res. 2013; 251: 25-34
        • Meyza K.Z.
        • Blanchard D.C.
        The BTBR mouse model of idiopathic autism - Current view on mechanisms.
        Neurosci. Biobehav. Rev. 2017;
        • Zilkha N.
        • Kuperman Y.
        • Kimchi T.
        High-fat diet exacerbates cognitive rigidity and social deficiency in the BTBR mouse model of autism.
        Neuroscience. 2016;
        • Smith T.
        • Weston C.
        • Lieberman J.
        Schizophrenia (maintenance treatment).
        Am. Fam. Physician. 2010; 82: 338-339
        • Morgese M.G.
        • Trabace L.
        Maternal malnutrition in the etiopathogenesis of psychiatric diseases: role of polyunsaturated fatty acids.
        Brain Sci. 2016; 6
        • McNamara R.K.
        • Jandacek R.
        • Rider T.
        • Tso P.
        • Dwivedi Y.
        • Pandey G.N.
        Adult medication-free schizophrenic patients exhibit long-chain omega-3 fatty acid deficiency: implications for cardiovascular disease risk.
        Cardiovasc Psychiatry Neurol. 2013; 2013: 796462
        • Solberg D.K.
        • Bentsen H.
        • Refsum H.
        • Andreassen O.A.
        Lipid profiles in schizophrenia associated with clinical traits: a five year follow-up study.
        BMC Psychiatry. 2016; 16: 299
        • McEvoy J.
        • Baillie R.A.
        • Zhu H.
        • Buckley P.
        • Keshavan M.S.
        • Nasrallah H.A.
        • Dougherty G.G.
        • Yao J.K.
        • Kaddurah-Daouk R.
        Lipidomics reveals early metabolic changes in subjects with schizophrenia: effects of atypical antipsychotics.
        PLoS One. 2013; 8: e68717
        • Yao J.K.
        Peet M. Glen I. Horrobin D.F. Abnormalities of Fatty Acid Metabolism in Red Cells, Platelets and Brain in Schizophrenia. Phospholipid Spectrum Disorders in Psychiatry and Neurology Marius Press, Lancashire, UK2003: 193-212
        • Perica M.M.
        • Delas I.
        Essential fatty acids and psychiatric disorders.
        Nutr. Clin. Pract. 2011; 26: 409-425
        • Hedelin M.
        • Lof M.
        • Olsson M.
        • Lewander T.
        • Nilsson B.
        • Hultman C.M.
        • Weiderpass E.
        Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population.
        BMC Psychiatry. 2010; 10: 38
        • Fenton W.S.
        • Hibbeln J.
        • Knable M.
        Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia.
        Biol. Psychiatry. 2000; 47: 8-21
        • Condray R.
        • Yao J.K.
        Cognition, dopamine and bioactive lipids in schizophrenia.
        Front. Biosci. (Sch. Ed.). 2011; 3: 298-330
        • Berger G.E.
        • Proffitt T.M.
        • McConchie M.
        • Yuen H.
        • Wood S.J.
        • Amminger G.P.
        • Brewer W.
        • McGorry P.D.
        Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial.
        J. Clin. Psychiatry. 2007; 68: 1867-1875
        • Richardson A.J.
        • Easton T.
        • Puri B.K.
        Red cell and plasma fatty acid changes accompanying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid.
        Eur. Neuropsychopharmacol. 2000; 10: 189-193
        • Reddy R.
        • Fleet-Michaliszyn S.
        • Condray R.
        • Yao J.K.
        • Keshavan M.S.
        • Reddy R.
        Reduction in perseverative errors with adjunctive ethyl-eicosapentaenoic acid in patients with schizophrenia: preliminary study.
        Prostaglandins Leukot. Ess. Fat. Acids. 2011; 84: 79-83
        • Yao J.K.
        • Reddy R.
        Oxidative stress in schizophrenia: pathogenetic and therapeutic implications.
        Antioxid. Redox Signal. 2011; 15: 1999-2002
        • Pawelczyk T.
        • Grancow-Grabka M.
        • Kotlicka-Antczak M.
        • Trafalska E.
        • Pawelczyk A.
        A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia.
        J. Psychiatr. Res. 2016; 73: 34-44
        • McNamara R.K.
        • Jandacek R.
        • Tso P.
        • Blom T.J.
        • Welge J.A.
        • Strawn J.R.
        • Adler C.M.
        • Strakowski S.M.
        • DelBello M.P.
        Adolescents with or at ultra-high risk for bipolar disorder exhibit erythrocyte docosahexaenoic acid and eicosapentaenoic acid deficits: a candidate prodromal risk biomarker.
        Early Inter. Psychiatry. 2016; 10: 203-211
        • Messamore E.
        • Almeida D.M.
        • Jandacek R.J.
        • McNamara R.K.
        Polyunsaturated fatty acids and recurrent mood disorders: phenomenology, mechanisms, and clinical application.
        Prog. Lipid Res. 2017; 66: 1-13
        • Grosso G.
        • Micek A.
        • Marventano S.
        • Castellano S.
        • Mistretta A.
        • Pajak A.
        • Galvano F.
        Dietary n-3 PUFA, fish consumption and depression: a systematic review and meta-analysis of observational studies.
        J. Affect. Disord. 2016; 205: 269-281
        • Carabelli B.
        • Delattre A.M.
        • Pudell C.
        • Mori M.A.
        • Suchecki D.
        • Machado R.B.
        • Venancio D.P.
        • Piazzetta S.R.
        • Hammerschmidt I.
        • Zanata S.M.
        • Lima M.M.
        • Zanoveli J.M.
        • Ferraz A.C.
        The antidepressant-like effect of fish oil: possible role of ventral hippocampal 5-HT1A post-synaptic receptor.
        Mol. Neurobiol. 2015; 52: 206-215
        • Patrick R.P.
        • Ames B.N.
        Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior.
        FASEB J. 2015; 29: 2207-2222
        • Freeman M.P.
        • Hibbeln J.R.
        • Wisner K.L.
        • Davis J.M.
        • Mischoulon D.
        • Peet M.
        • Keck Jr., P.E.
        • Marangell L.B.
        • Richardson A.J.
        • Lake J.
        • Stoll A.L.
        Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry.
        J. Clin. Psychiatry. 2006; 67: 1954-1967
        • Amminger G.P.
        • Schafer M.R.
        • Papageorgiou K.
        • Klier C.M.
        • Cotton S.M.
        • Harrigan S.M.
        • Mackinnon A.
        • McGorry P.D.
        • Berger G.E.
        Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial.
        Arch. Gen. Psychiatry. 2010; 67: 146-154
        • Amminger G.P.
        • Schafer M.R.
        • Schlogelhofer M.
        • Klier C.M.
        • McGorry P.D.
        Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study.
        Nat. Commun. 2015; 6: 7934
        • Mechelli A.
        • Lin A.
        • Wood S.
        • McGorry P.
        • Amminger P.
        • Tognin S.
        • McGuire P.
        • Young J.
        • Nelson B.
        • Yung A.
        Using clinical information to make individualized prognostic predictions in people at ultra high risk for psychosis.
        Schizophr. Res. 2016;
        • Schlogelhofer M.
        • Amminger G.P.
        • Schaefer M.R.
        • Fusar-Poli P.
        • Smesny S.
        • McGorry P.
        • Berger G.
        • Mossaheb N.
        Polyunsaturated fatty acids in emerging psychosis: a safer alternative?.
        Early Inter. Psychiatry. 2014; 8: 199-208
        • Harris W.S.
        Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor.
        Pharm. Res. 2007; 55: 217-223
        • Harris W.S.
        • Miller M.
        • Tighe A.P.
        • Davidson M.H.
        • Schaefer E.J.
        Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives.
        Atherosclerosis. 2008; 197: 12-24
        • Jacobson T.A.
        • Glickstein S.B.
        • Rowe J.D.
        • Soni P.N.
        Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review.
        J. Clin. Lipidol. 2012; 6: 5-18
        • Yao J.K.
        • Dougherty G.G.
        • Reddy R.D.
        • Matson W.R.
        • Kaddurah-Daouk R.
        • Keshavan M.S.
        Associations between purine metabolites and monoamine neurotransmitters in first-episode psychosis.
        Front. Cell Neurosci. 2013; 7: 90
        • Emsley R.
        • Niehaus D.J.
        • Oosthuizen P.P.
        • Koen L.
        • Ascott-Evans B.
        • Chiliza B.
        • van Rensburg S.J.
        • Smit R.M.
        Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo-controlled trial.
        Psychiatry Res. 2008; 161: 284-291
        • Messamore J.K.
        • Yao E.
        Phospholipid, arachidonate and eicosanoid signaling in schizophrenia.
        Oilseeds Fats Corps Lipids. 2016; 23: D112
        • Yao J.K.
        • Dougherty Jr., G.G.
        • Gautier C.H.
        • Haas G.L.
        • Condray R.
        • Kasckow J.W.
        • Kisslinger B.L.
        • Gurklis J.A.
        • Messamore E.
        Prevalence and specificity of the abnormal niacin response: a potential endophenotype marker in schizophrenia.
        Schizophr. Bull. 2016; 42: 369-376
        • Keshavan M.S.
        • Anderson S.
        • Pettegrew J.W.
        Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited.
        J. Psychiatr. Res. 1994; 28: 239-265
        • Sumiyoshi T.
        • Higuchi Y.
        • Matsui M.
        • Itoh H.
        • Uehara T.
        • Itoh T.
        • Arai H.
        • Takamiya C.
        • Suzuki M.
        • Kurachi M.
        Membrane fatty acid levels as a predictor of treatment response in chronic schizophrenia.
        Psychiatry Res. 2011; 186: 23-27
        • Zimmer L.
        • Delpal S.
        • Guilloteau D.
        • Aioun J.
        • Durand G.
        • Chalon S.
        Chronic n-3 polyunsaturated fatty acid deficiency alters dopamine vesicle density in the rat frontal cortex.
        Neurosci. Lett. 2000; 284: 25-28
        • Fedorova I.
        • Hussein N.
        • Baumann M.H.
        • Di Martino C.
        • Salem Jr., N.
        An n-3 fatty acid deficiency impairs rat spatial learning in the Barnes maze.
        Behav. Neurosci. 2009; 123: 196-205
        • Chalon S.
        Omega-3 fatty acids and monoamine neurotransmission.
        Prostaglandins Leukot. Ess. Fat. Acids. 2006; 75: 259-269
        • du Bois T.M.
        • Deng C.
        • Huang X.F.
        Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia.
        Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005; 29: 878-888
        • Ohara K.
        The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia.
        Prog. Neuropsychopharmacol. Biol. Psychiatry. 2007; 31: 469-474
        • van der Kemp W.J.
        • Klomp D.W.
        • Kahn R.S.
        • Luijten P.R.
        • Pol H.E. Hulshoff
        A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia.
        Schizophr. Res. 2012; 141: 153-161
        • Hoen W.P.
        • Lijmer J.G.
        • Duran M.
        • Wanders R.J.
        • van Beveren N.J.
        • de Haan L.
        Red blood cell polyunsaturated fatty acids measured in red blood cells and schizophrenia: a meta-analysis.
        Psychiatry Res. 2013; 207: 1-12
        • Medema S.
        • Mocking R.J.
        • Koeter M.W.
        • Vaz F.M.
        • Meijer C.
        • de Haan L.
        • van Beveren N.J.
        • Group
        • Genetic R.
        • Outcome of Psychosis i.
        • Kahn R.
        • de Haan L.
        • van Os J.
        • Wiersma D.
        • Bruggeman R.
        • Cahn W.
        • Meijer C.
        • Myin-Germeys I.
        Levels of red blood cell fatty acids in patients With psychosis, their unaffected siblings, and healthy controls.
        Schizophr. Bull. 2016; 42: 358-368
        • Bentsen H.
        • Solberg D.K.
        • Refsum H.
        • Gran J.M.
        • Bohmer T.
        • Torjesen P.A.
        • Halvorsen O.
        • Lingjaerde O.
        Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder.
        Biol. Psychiatry. 2011; 70: 97-105
        • Bentsen H.
        • Osnes K.
        • Refsum H.
        • Solberg D.K.
        • Bohmer T.
        A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia.
        Transl. Psychiatry. 2013; 3: e335
        • Stillwell W.
        • Wassall S.R.
        Docosahexaenoic acid: membrane properties of a unique fatty acid.
        Chem. Phys. Lipids. 2003; 126: 1-27
        • Guixa-Gonzalez R.
        • Javanainen M.
        • Gomez-Soler M.
        • Cordobilla B.
        • Domingo J.C.
        • Sanz F.
        • Pastor M.
        • Ciruela F.
        • Martinez-Seara H.
        • Selent J.
        Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors.
        Sci. Rep. 2016; 6: 19839
        • Sugasini D.
        • Lokesh B.R.
        Rats given linseed oil in microemulsion forms enriches the brain synaptic membrane with docosahexaenoic acid and enhances the neurotransmitter levels in the brain.
        Nutr. Neurosci. 2015; 18: 87-96
        • Hashimoto M.
        • Hossain S.
        • Shimada T.
        • Shido O.
        Docosahexaenoic acid-induced protective effect against impaired learning in amyloid beta-infused rats is associated with increased synaptosomal membrane fluidity.
        Clin. Exp. Pharm. Physiol. 2006; 33: 934-939
        • Sublimi Saponetti M.
        • Grimaldi M.
        • Scrima M.
        • Albonetti C.
        • Nori S.L.
        • Cucolo A.
        • Bobba F.
        • D'Ursi A.M.
        Aggregation of Ass(25-35) on DOPC and DOPC/DHA bilayers: an atomic force microscopy study.
        PLoS One. 2014; 9: e115780
        • Eckert G.P.
        • Chang S.
        • Eckmann J.
        • Copanaki E.
        • Hagl S.
        • Hener U.
        • Muller W.E.
        • Kogel D.
        • Liposome-incorporated
        DHA increases neuronal survival by enhancing non-amyloidogenic APP processing.
        Biochim. Biophys. Acta. 2011; 1808: 236-243
        • Yang X.
        • Sheng W.
        • Sun G.Y.
        • Lee J.C.
        Effects of fatty acid unsaturation numbers on membrane fluidity and alpha-secretase-dependent amyloid precursor protein processing.
        Neurochem. Int. 2011; 58: 321-329
        • Wellhauser L.
        • Belsham D.D.
        Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons.
        J. Neuroinflamm. 2014; 11: 60
        • Tremblay M.E.
        • Zhang I.
        • Bisht K.
        • Savage J.C.
        • Lecours C.
        • Parent M.
        • Titorenko V.
        • Maysinger D.
        Remodeling of lipid bodies by docosahexaenoic acid in activated microglial cells.
        J. Neuroinflamm. 2016; 13: 116
        • Hong S.
        • Lu Y.
        • Yang R.
        • Gotlinger K.H.
        • Petasis N.A.
        • Serhan C.N.
        Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms.
        J. Am. Soc. Mass Spectrom. 2007; 18: 128-144
        • Rey C.
        • Nadjar A.
        • Buaud B.
        • Vaysse C.
        • Aubert A.
        • Pallet V.
        • Laye S.
        • Joffre C.
        Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro.
        Brain Behav. Immun. 2016; 55: 249-259
        • Serhan C.N.
        • Gotlinger K.
        • Hong S.
        • Arita M.
        Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis.
        Prostaglandins Other Lipid Mediat. 2004; 73: 155-172
        • Bazan N.G.
        The docosanoid neuroprotectin D1 induces homeostatic regulation of neuroinflammation and cell survival.
        Prostaglandins Leukot. Ess. Fat. Acids. 2013; 88: 127-129
        • Bazan N.G.
        Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress.
        Brain Pathol. 2005; 15: 159-166
        • Bazan N.G.
        • Eady T.N.
        • Khoutorova L.
        • Atkins K.D.
        • Hong S.
        • Lu Y.
        • Zhang C.
        • Jun B.
        • Obenaus A.
        • Fredman G.
        • Zhu M.
        • Winkler J.W.
        • Petasis N.A.
        • Serhan C.N.
        • Belayev L.
        Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke.
        Exp. Neurol. 2012; 236: 122-130
        • Serhan C.N.
        • Fredman G.
        • Yang R.
        • Karamnov S.
        • Belayev L.S.
        • Bazan N.G.
        • Zhu M.
        • Winkler J.W.
        • Petasis N.A.
        Novel proresolving aspirin-triggered DHA pathway.
        Chem. Biol. 2011; 18: 976-987
        • Eady T.N.
        • Belayev L.
        • Khoutorova L.
        • Atkins K.D.
        • Zhang C.
        • Bazan N.G.
        Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats.
        PLoS One. 2012; 7: e46151
        • Hashimoto M.
        • Katakura M.
        • Tanabe Y.
        • Al Mamun A.
        • Inoue T.
        • Hossain S.
        • Arita M.
        • Shido O.
        n-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acid-derived docosanoids in aged rats.
        Biochim. Biophys. Acta. 2015; 1851: 203-209
        • Wu A.
        • Ying Z.
        • Gomez-Pinilla F.
        Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.
        J. Neurotrauma. 2004; 21: 1457-1467
        • Rao J.S.
        • Ertley R.N.
        • Lee H.J.
        • DeMar Jr., J.C.
        • Arnold J.T.
        • Rapoport S.I.
        • Bazinet R.P.
        N-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism.
        Mol. Psychiatry. 2007; 12: 36-46
        • Gan L.
        • Johnson J.A.
        Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases.
        Biochim. Biophys. Acta. 2014; 1842: 1208-1218
        • Gao B.
        • Doan A.
        • Hybertson B.M.
        The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders.
        Clin. Pharmacol. 2014; 6: 19-34
        • Zhang D.D.
        • Lo S.C.
        • Cross J.V.
        • Templeton D.J.
        • Hannink M.
        Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex.
        Mol. Cell Biol. 2004; 24: 10941-10953
        • Scapagnini G.
        • Vasto S.
        • Abraham N.G.
        • Caruso C.
        • Zella D.
        • Fabio G.
        Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders.
        Mol. Neurobiol. 2011; 44: 192-201
        • Sandberg M.
        • Patil J.
        • D'Angelo B.
        • Weber S.G.
        • Mallard C.
        NRF2-regulation in brain health and disease: implication of cerebral inflammation.
        Neuropharmacology. 2014; 79: 298-306
        • Kusunoki C.
        • Yang L.
        • Yoshizaki T.
        • Nakagawa F.
        • Ishikado A.
        • Kondo M.
        • Morino K.
        • Sekine O.
        • Ugi S.
        • Nishio Y.
        • Kashiwagi A.
        • Maegawa H.
        Omega-3 polyunsaturated fatty acid has an anti-oxidant effect via the Nrf-2/HO-1 pathway in 3T3-L1 adipocytes.
        Biochem. Biophys. Res. Commun. 2013; 430: 225-230
        • Guichardant M.
        • Bacot S.
        • Moliere P.
        • Lagarde M.
        Hydroxy-alkenals from the peroxidation of n-3 and n-6 fatty acids and urinary metabolites.
        Prostaglandins Leukot. Ess. Fat. Acids. 2006; 75: 179-182
        • Riahi Y.
        • Cohen G.
        • Shamni O.
        • Sasson S.
        Signaling and cytotoxic functions of 4-hydroxyalkenals.
        Am. J. Physiol. Endocrinol. Metab. 2010; 299: E879-E886
        • Chen Z.H.
        • Yoshida Y.
        • Saito Y.
        • Noguchi N.
        • Niki E.
        Adaptive response induced by lipid peroxidation products in cell cultures.
        FEBS Lett. 2006; 580: 479-483
        • Chen Z.H.
        • Saito Y.
        • Yoshida Y.
        • Sekine A.
        • Noguchi N.
        • Niki E.
        4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2.
        J. Biol. Chem. 2005; 280: 41921-41927
        • Nakagawa F.
        • Morino K.
        • Ugi S.
        • Ishikado A.
        • Kondo K.
        • Sato D.
        • Konno S.
        • Nemoto K.
        • Kusunoki C.
        • Sekine O.
        • Sunagawa A.
        • Kawamura M.
        • Inoue N.
        • Nishio Y.
        • Maegawa H.
        4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs.
        Biochem. Biophys. Res. Commun. 2014; 443: 991-996
        • Kondo K.
        • Morino K.
        • Nishio Y.
        • Kondo M.
        • Nakao K.
        • Nakagawa F.
        • Ishikado A.
        • Sekine O.
        • Yoshizaki T.
        • Kashiwagi A.
        • Ugi S.
        • Maegawa H.
        A fish-based diet intervention improves endothelial function in postmenopausal women with type 2 diabetes mellitus: a randomized crossover trial.
        Metabolism. 2014; 63: 930-940
        • Ishikado A.
        • Nishio Y.
        • Morino K.
        • Ugi S.
        • Kondo H.
        • Makino T.
        • Kashiwagi A.
        • Maegawa H.
        Low concentration of 4-hydroxy hexenal increases heme oxygenase-1 expression through activation of Nrf2 and antioxidative activity in vascular endothelial cells.
        Biochem. Biophys. Res. Commun. 2010; 402: 99-104
        • Huang Y.
        • Li W.
        • Kong A.N.
        Anti-oxidative stress regulator NF-E2-related factor 2 mediates the adaptive induction of antioxidant and detoxifying enzymes by lipid peroxidation metabolite 4-hydroxynonenal.
        Cell Biosci. 2012; 2: 40
        • Ishikado A.
        • Morino K.
        • Nishio Y.
        • Nakagawa F.
        • Mukose A.
        • Sono Y.
        • Yoshioka N.
        • Kondo K.
        • Sekine O.
        • Yoshizaki T.
        • Ugi S.
        • Uzu T.
        • Kawai H.
        • Makino T.
        • Okamura T.
        • Yamamoto M.
        • Kashiwagi A.
        • Maegawa H.
        4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.
        PLoS One. 2013; 8: e69415
        • Cipollina C.
        Endogenous generation and signaling actions of omega-3 fatty acid electrophilic derivatives.
        Biomed. Res. Int. 2015; 2015: 501792
        • Csala M.
        • Kardon T.
        • Legeza B.
        • Lizak B.
        • Mandl J.
        • Margittai E.
        • Puskas F.
        • Szaraz P.
        • Szelenyi P.
        • Banhegyi G.
        On the role of 4-hydroxynonenal in health and disease.
        Biochim. Biophys. Acta. 2015; 1852: 826-838
        • Schaur R.J.
        • Siems W.
        • Bresgen N.
        • Eckl P.M.
        4-hydroxy-nonenal-A bioactive lipid peroxidation product.
        Biomolecules. 2015; 5: 2247-2337
        • Long E.K.
        • Picklo Sr., M.J.
        Trans-4-hydroxy-2-hexenal, a product of n-3 fatty acid peroxidation: make some room HNE.
        Free Radic. Biol. Med. 2010; 49: 1-8
        • Cipollina C.
        • Di Vincenzo S.
        • Gerbino S.
        • Siena L.
        • Gjomarkaj M.
        • Pace E.
        Dual anti-oxidant and anti-inflammatory actions of the electrophilic cyclooxygenase-2-derived 17-oxo-DHA in lipopolysaccharide- and cigarette smoke-induced inflammation.
        Biochim. Biophys. Acta. 2014; 1840: 2299-2309
        • Sun G.Y.
        • Chen Z.
        • Jasmer K.J.
        • Chuang D.Y.
        • Gu Z.
        • Hannink M.
        • Simonyi A.
        Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1.
        PLoS One. 2015; 10: e0141509
        • Sun G.Y.
        • Li R.
        • Cui J.
        • Hannink M.
        • Gu Z.
        • Fritsche K.L.
        • Lubahn D.B.
        • Simonyi A.
        Withania somnifera and its withanolides attenuate oxidative and inflammatory responses and up-regulate antioxidant responses in BV-2 microglial cells.
        Neuromolecular Med. 2016; 18: 241-252
        • Ajit D.
        • Simonyi A.
        • Li R.
        • Chen Z.
        • Hannink M.
        • Fritsche K.L.
        • Mossine V.V.
        • Smith R.E.
        • Dobbs T.K.
        • Luo R.
        • Folk W.R.
        • Gu Z.
        • Lubahn D.B.
        • Weisman G.A.
        • Sun G.Y.
        Phytochemicals and botanical extracts regulate NF-kappaB and Nrf2/ARE reporter activities in DI TNC1 astrocytes.
        Neurochem. Int. 2016; 97: 49-56
        • Gatbonton-Schwager T.N.
        • Sadhukhan S.
        • Zhang G.F.
        • Letterio J.J.
        • Tochtrop G.P.
        Identification of a negative feedback loop in biological oxidant formation fegulated by 4-hydroxy-2-(E)-nonenal.
        Redox Biol. 2014; 2: 755-763
        • Farias J.G.
        • Carrasco-Pozo C.
        • Carrasco Loza R.
        • Sepulveda N.
        • Alvarez P.
        • Quezada M.
        • Quinones J.
        • Molina V.
        • Castillo R.L.
        Polyunsaturated fatty acid induces cardioprotection against ischemia-reperfusion through the inhibition of NF-kappaB and induction of Nrf2.
        Exp. Biol. Med. 2016;
        • Cipollina C.
        • Salvatore S.R.
        • Muldoon M.F.
        • Freeman B.A.
        • Schopfer F.J.
        Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives.
        PLoS One. 2014; 9: e94836
        • Bu J.
        • Dou Y.
        • Tian X.
        • Wang Z.
        • Chen G.
        The role of omega-3 polyunsaturated fatty acids in stroke.
        Oxid. Med. Cell Longev. 2016; 2016: 6906712
        • Anthonymuthu T.S.
        • Kenny E.M.
        • Bayir H.
        Therapies targeting lipid peroxidation in traumatic brain injury.
        Brain Res. 2016; 1640: 57-76
        • Begum G.
        • Harvey L.
        • Dixon C.E.
        • Sun D.
        ER stress and effects of DHA as an ER stress inhibitor.
        Transl. Stroke Res. 2013; 4: 635-642
        • Pu H.
        • Guo Y.
        • Zhang W.
        • Huang L.
        • Wang G.
        • Liou A.K.
        • Zhang J.
        • Zhang P.
        • Leak R.K.
        • Wang Y.
        • Chen J.
        • Gao Y.
        Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury.
        J. Cereb. Blood Flow. Metab. 2013; 33: 1474-1484
        • Figueroa J.D.
        • Cordero K.
        • Llan M.S.
        • De Leon M.
        Dietary omega-3 polyunsaturated fatty acids improve the neurolipidome and restore the DHA status while promoting functional recovery after experimental spinal cord injury.
        J. Neurotrauma. 2013; 30: 853-868
        • Paterniti I.
        • Impellizzeri D.
        • Di Paola R.
        • Esposito E.
        • Gladman S.
        • Yip P.
        • Priestley J.V.
        • Michael-Titus A.T.
        • Cuzzocrea S.
        Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies.
        J. Neuroinflamm. 2014; 11: 6
        • Chang C.Y.
        • Kuan Y.H.
        • Li J.R.
        • Chen W.Y.
        • Ou Y.C.
        • Pan H.C.
        • Liao S.L.
        • Raung S.L.
        • Chang C.J.
        • Chen C.J.
        Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats.
        J. Nutr. Biochem. 2013; 24: 2127-2137
        • Zhang M.
        • Wang S.
        • Mao L.
        • Leak R.K.
        • Shi Y.
        • Zhang W.
        • Hu X.
        • Sun B.
        • Cao G.
        • Gao Y.
        • Xu Y.
        • Chen J.
        • Zhang F.
        Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1.
        J. Neurosci. 2014; 34: 1903-1915
        • Zhang W.
        • Zhang H.
        • Mu H.
        • Zhu W.
        • Jiang X.
        • Hu X.
        • Shi Y.
        • Leak R.K.
        • Dong Q.
        • Chen J.
        • Gao Y.
        Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury.
        Neurobiol. Dis. 2016; 91: 37-46
        • Lim S.N.
        • Gladman S.J.
        • Dyall S.C.
        • Patel U.
        • Virani N.
        • Kang J.X.
        • Priestley J.V.
        • Michael-Titus A.T.
        Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury.
        Neurobiol. Dis. 2013; 51: 104-112
        • Lim S.N.
        • Huang W.
        • Hall J.C.
        • Michael-Titus A.T.
        • Priestley J.V.
        Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid.
        Exp. Neurol. 2013; 239: 13-27
        • Harvey L.D.
        • Yin Y.
        • Attarwala I.Y.
        • Begum G.
        • Deng J.
        • Yan H.Q.
        • Dixon C.E.
        • Sun D.
        Administration of DHA reduces endoplasmic reticulum stress-associated inflammation and alters microglial or macrophage activation in traumatic brain injury.
        ASN Neuro. 2015; 7
        • Derosa G.
        • Cicero A.F.
        • Fogari E.
        • D'Angelo A.
        • Bonaventura A.
        • Romano D.
        • Maffioli P.
        Effects of n-3 PUFAs on postprandial variation of metalloproteinases, and inflammatory and insulin resistance parameters in dyslipidemic patients: evaluation with euglycemic clamp and oral fat load.
        J. Clin. Lipidol. 2012; 6: 553-564
        • Pusceddu M.M.
        • Kelly P.
        • Stanton C.
        • Cryan J.F.
        • Dinan T.G.
        N-3 polyunsaturated fatty acids through the lifespan: implication for psychopathology.
        Int. J. Neuropsychopharmacol. 2016;
        • Wu A.
        • Noble E.E.
        • Tyagi E.
        • Ying Z.
        • Zhuang Y.
        • Gomez-Pinilla F.
        Curcumin boosts DHA in the brain: implications for the prevention of anxiety disorders.
        Biochim. Biophys. Acta. 2015; 1852: 951-961
        • Shalini S.M.
        • Herr D.R.
        • Ong W.Y.
        The analgesic and anxiolytic effect of Souvenaid, a novel nutraceutical, Is mediated by Alox15 activity in the prefrontal cortex.
        Mol. Neurobiol. 2016;