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The Anti-Oxidative Component of Docosahexaenoic Acid (DHA) in the Brain in Diabetes
C H A P T E R
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The Anti-Oxidative Component of Docosahexaenoic Acid (DHA) in the Brain in Diabetes Emma Arnal*, María Miranda**, Siv Johnsen-Soriano*, Francisco J. Romero*, † *Fundación Oftalmológica del Mediterráneo, Valencia, Spain, **Universidad CEU Cardenal Herrera, Moncada, Spain, †Facultad de Medicina, Universidad Católica de Valencia ‘San Vicente Mártir’, Valencia, Spain
List of Abbreviations AA Arachidonic acid ALA Alfa-linolenic acid ARPE-19 Human retinal pigment epithelial cell line CNS Central nervous system COX Cyclooxygenase DHA Docosahexaenoic acid EPA Eicosapentanoic acid GSH Glutathione IL Interleukin LOX Lipoxygenase MCI Mild cognitive impairment NPD1 Neuroprotectin D1 PUFA Polyunsaturated fatty acid ROS Reactive oxygen species RPE Retinal pigment epithelium SOD Superoxide dismutase
INTRODUCTION: OXIDATIVE STRESS IN DIABETES Neuronal cells are particularly sensitive to oxidative insults, and reactive oxygen species (ROS) are involved in many neurodegenerative processes such as diabetes [1–3]. In these pathological conditions, cellular stress triggers mitochondrial oxidative damage, which may result in apoptosis and/or necrosis [4], and apoptosis induced by oxidative stress has been related to neurogenesis inhibition [5]. ROS generated by high glucose levels causes metabolic abnormalities which are involved in the development of
Diabetes: Oxidative Stress and Dietary Antioxidants. http://dx.doi.org/10.1016/B978-0-12-405885-9.00013-9
diabetes [6]. Previous studies have shown that oxidative stress is closely linked to apoptosis in a variety of cell types under hyperglycemic conditions [7]; furthermore apoptosis mediated by caspase-3 is activated in the brain of diabetic rats, and antioxidants are able to inhibit these activations [8–10] (Figure 13.1). Chronic degenerative brain disease in diabetes, known as 'diabetic encephalopathy', is a recognized complication that can occur in patients whose diabetes is long-standing. The mechanisms underlying diabetic encephalopathy are only partially understood, and can involve impairments in learning, memory, problem solving, and mental and motor speed (Figure 13.2) which are more common in type 1 diabetic patients than in the general population [11]. Neuronal cells are particularly sensitive to oxidative insults and ROS are involved in many neurodegenerative processes (not only diabetes but also Alzheimer's, Parkinson's, and Huntington's diseases, acute brain ischemia, and excitotoxicity) [1–3]. The possible source of oxidative stress in brain injury includes auto-oxidation of glucose, lipid peroxidation, decreased tissue concentrations of low molecular weight antioxidants such as reduced glutathione (GSH) (Figure 13.3) and impaired activities of antioxidant defense enzymes such as superoxide dismutase (SOD) and catalase [6,12,13]. Convincing evidence is now available from previous studies to prove the role of oxidative stress in the development of neuronal injury in the diabetic brain and the beneficial effects of antioxidants.
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Copyright © 2014 Elsevier Inc. All rights reserved.
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13. THE ANTI-OXIDATIVE COMPONENT OF DOCOSAHEXAENOIC ACID (DHA) IN THE BRAIN IN DIABETES
FIGURE 13.1 Number of TUNEL-positive cells in the dentate gyrus of the hippocampus of diabetic and control rats. (*p < 0.05 vs. all groups). C, control; D, untreated diabetic rats; DI, diabetic rats treated with insulin.
FIGURE 13.2 Schematic representation of the potential impairments in diabetic encephalopathy.
However clinical trials testing the efficacy of antioxidants in the treatment of different diseases, including diabetes, have produced contradictory findings. This could be because most studies have focused on the use of antioxidants to block the production of ROS and other compounds, and perhaps it is too late to observe any beneficial effect and focus should be placed on blocking changes in intracellular signaling produced by oxidative stress. In this sense, many studies demonstrate the ability of antioxidant administration to revert the perjudicial effects of diabetes. The beneficial effect of lutein and DHA in diabetic animals and the way that these substances were able to ameliorate the oxidative stress present in diabetes have been studied [14].
DOCOSAHEXAENOIC ACID (DHA) DHA;4 22:6(n-3) (Figure 13.4); is a dietary essential (n-3) PUFA highly enriched in fish oils and concentrated up the food chain from photosynthetic and heterotrophic microalgae. In addition to these essential marine sources, DHA is also synthesized via the elongation and desaturation of the 20-carbon eicosapentanoic acid (EPA 20:5(n-3)), or by elongation of the 18-carbon (n-3) fatty acid, a-linolenic acid (ALA; 18:3 ( n-3)) enriched in flax (Linaceae), walnut (Juglandaceae), chia (Salvia hispanica), and other photosynthesizing terrestrial plants (Figure 13.5) [15–17]. In the brain, the glial and endothelial cells of the microvasculature, but not neurons, have some capacity to synthesize DHA from ALA and other (n-3) precursor fatty acids, but whether or not this contributes significantly to total brain DHA is not clear. The high concentration of DHA in the capillary endothelium suggests that DHA is taken up from the diet via
FIGURE 13.3 GSH concentration in the cortex and hippocampus of control and 4 or 12 weeks diabetic rats (*p < 0.05 vs. control 12 weeks groups). C, control; D, untreated diabetic rats.
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DHA and Oxidative Stress
FIGURE 13.4 DHA structure.
FIGURE 13.5 Eicosapentanoic acid and α-linolenic acid structures.
blood plasma DHA transporters including specific fatty-acid-binding lipoprotein carriers [17–19]. DHA is an absolute requirement for the development of the human central nervous system (CNS), and the continuous maintenance of brain cell function, illustrating the strong mechanistic link between an adequate supply of essential PUFA in the diet and the sustenance of cognitive health. During postnatal development, rapid accretion of DHA in the brain and retina takes place [16–18]. DHA attains its highest concentration in CNS synapses and in retinal photoreceptors; in fact, up to 60% of all fatty acids esterified in neuronal plasma membrane phospholipid consist of DHA. By means of a postnatal mouse development experimental model, it has been determined that dietary ALA is first taken up by the liver, where elongation and desaturation to DHA occurs, followed by its supply through the bloodstream to brain and retina, coinciding with photoreceptor development and synaptogenesis [17,19]. Brain and retinal cells therefore have a convenient and readily accessible supply of DHA that, through highly regulated, phospholipase-mediated exoprotease activities, liberates membrane-bound DHA to serve in neuroprotective and cell fate-signaling roles [20–26]. The beneficial neurophysiological actions of DHA occur in part through its direct maintenance of neuronal plasma membrane fluidity and functional integrity, and in part through the generation of docosanoids. The first identified DHA-derived mediator, neuroprotectin D1 (NPD1; MW 359), is formed through tandem phospholipase A2 (PLA2)-lipoxygenase (LOX) action on free DHA, via a 16,17S-DHA epoxide intermediate [20,24,27,28].
DHA AND OXIDATIVE STRESS DHA is most highly concentrated in photoreceptors, the nervous system, and testes, in descending order of concentration [26]. Both neurons and glia are richly endowed with this fatty acid. The outer segments of photoreceptors
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display the highest content of DHA in the human body. Moreover, DHA is present in much smaller quantities in non-nervous system cells. DHA is esterified at C2 of the glycerol backbone of phospholipids. In contrast the other major polyunsaturated fatty acyl group of cell phospholipids, the omega-6 family member arachidonic acid (AA), is distributed throughout the human body. Arachidonoyl chains of phospholipids are the reservoir of biologically active eicosanoids, and docosahexaenoyl chains of phospholipids are a reservoir for biologically active docosanoids. Both polyunsaturated fatty acids are also a target for free radical-mediated lipid peroxidation. Free (unesterified) AA and DHA are released from membrane phospholipids through the action of phospholipases in response to stimulation (e.g., neurotransmitters, cytokines, seizures, ischemia, neurotrauma, etc.) [26,29]. This response tells us that phospholipases are a regulatory gatekeeper in the initiation of the eicosanoid and docosanoid pathways under both physiological and pathological conditions. It remains to be determined whether any of the docosanoids are esterified back into phospholipids, which might, in turn, serve as reservoirs for readily-made bioactive mediators. In connection with this, there are examples of AA-derived lipoxygenation products incorporated into phospholipids of the nervous tissue [30]. During basal cell function, active ATP-dependent reacylation of AA and DHA takes place in membrane phospholipids [31,32]. Oxidative stress in the brain generates neuroprostanes from DHA through enzyme-independent reactions [33]. It has recently been shown that electrophilic cyclopentenone neuroprostanes elicit anti-inflammatory activity [34]. These compounds are formed from the peroxidation of DHA; therefore, it remains to be determined how the production of these compounds might be regulated and how they might exert specific actions such as antiinflammatory activity. DHA is required for brain and retina development [35] and has been implicated in several functions, including those of excitable membranes [36,37], memory [37], photoreceptor biogenesis and function [38], and neuroprotection [39]. One property the retina and brain share (insofar as omega-3 fatty acids are concerned) is their unusual ability to retain DHA even during prolonged dietary deprivation of essential fatty acids of the omega-3 family. To effectively reduce the DHA content in retinas and brains of rodents and non-human primates, dietary deprivation for more than one generation has been required [40,41]. This in turn produces impairments of retinal and brain function. Studies on DHA-mediated neuroprotection have prompted the following questions: Is the prosurvival action of DHA the result of replenishing the fatty acid into membrane phospholipids? Is it due to a more selective signaling by a DHA-derived mediator? Or is there a combination of mechanisms?
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This review highlights the elucidation of a specific DHA mediator that promotes the homeostatic regulation of cell integrity and retina and brain protection.
NEUROPROTECTIN D1 The retina forms mono-, di- and trihydroxy derivatives of DHA. Since lipoxygenase inhibitors block the formation of these derivatives, it was suggested that a lipoxygenase enzyme catalyzes their synthesis, and the name ‘docosanoids’ was introduced for the family of enzyme-derived products of DHA [42]. At the time of that study, the stereochemistry and bioactivity of these DHA-oxygenated derivatives were not defined. It was suggested, however, that these lipoxygenase-reaction products might be neuroprotective [42]. Upon the advent of mediator lipidomic analysis based on liquid chromatography, photodiode array, electrospray ionization, and tandem mass spectrometry (LC-MS/MS), Bazan and colleagues [43] identified oxygenation pathways for the synthesis of the stereospecific docosanoid NPD1 during brain ischemia-reperfusion [44], in human RPE cells [45–47], in human brain cells [20], and in the human brain. NPD1 synthesis occurs through DHA oxygenation by 15-lipoxygenase-1 (15-LOX-1). NPD1 then works through a stereospecific site, implying that this mediator acts in an autocrine fashion, and/or diffuses through the intercellular space (e.g., interphotoreceptor matrix to act in paracrine mode on nearby cells). One paracrine target in the retina could be photoreceptor cells and/or Müller cells. In addition, this group described the way that interleukin (IL)-1β, oxidative stress, or the Ca2+ ionophore A23187 activates the synthesis of NPD1 in ARPE19 cells (spontaneously transformed human RPE cells)
[45]. NPD1 in turn is a potent inhibitor of oxidativestress-induced apoptosis and of cytokine-mediated proinflammatory induction of cyclooxygenase 2 (COX-2). The name ‘neuroprotectin D1’ [47] was proposed, based on its neuroprotective bioactivity in oxidatively stressed RPE cells or brain and its potent ability to inactivate proapoptotic and pro-inflammatory signaling. ‘D1’ refers to this being the first identified neuroprotective mediator derived from DHA.
DHA AND OXIDATIVE STRESS IN THE BRAIN Oxidative stress results from an imbalance between the formation and the degradation of pro-oxidants or impaired cellular antioxidant mechanisms, and excessive oxidative stress leads to cell damage and apoptosis [48]. The brain is particularly susceptible to oxidative stress, because it has a high content of easily peroxidizable longchain PUFAs such as DHA and AA. Mitochondrial consumption of a large quantity of glucose to fuel the brain’s normal energy requirements also results in relatively high production of free radicals [49]. In diabetes, the oxidative stress situation increases the production of free radicals, resulting in increased lipid peroxidation in the brain [50]. Crucial oxidative damage has also been observed in subjects with mild cognitive impairment (MCI), suggesting an early role of oxidative stress [51]. Lipid peroxide levels are significantly lower in DHA-administered rats and reciprocally correlate with the DHA/AA ratio [52], indicating that dietary DHA contributes to the antioxidant defense, decreases oxidative stress, and protects against memory loss. This inference is consistent with the fact that DHA also increases the levels of antioxidant enzymes such as
FIGURE 13.6 Schematic representation of the potential DHA and NPD1 actions that may lead to apoptosis inhibition.
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catalase and glutathione peroxidase, and reduces glutathione levels with a concomitant decrease in the levels of ROS in the cortex and hippocampus of diabetes rat models [53]. Further, DHA has free radical-scavenging properties such as protection against lipid and protein peroxidation in developing and adult brains and attenuation of neuronal loss and cognitive and locomotor deficits in animal models of ischemia-reperfusion brain injury [54]. The antioxidant action of DHA in the brain has been underscored [55], despite the fact that its molecular structure contains six double bonds, which theoretically makes it a molecular target for peroxidation and sensitizes cells to ROS. Moreover, DHA can produce docosatrienes and resolvins, collectively known as docosanoids. In particular, NPD1 is formed through tandem phospholipase A2-lipoxygenase action on free DHA; it is a docosatriene that appears to be a major bioactive effector in neuronal tissues. Even a minute amount of NPD1 can promote anti-inflammatory and neuroprotective activity and inhibit oxidative stressinduced apoptosis [20] (Figure 13.6). These results suggest the notable role of DHA and/or DHA-derived mediators in the inhibition of oxidative stress.
References [1] Jackson GR, Werrbach-Perez K, Pan Z, Sampath D, Perez-Polo JR. Neurotrophin regulation of energy homeostasis in the central nervous system. Dev Neurosci 1994;16:285–90. [2] Dugan LL, Sensi SL, Canzoniero LM, Handran SD, Rothman SM, Lin TS, et al. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 1995;15:6377–88. [3] Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000;407:802–9. [4] Merad-Boudia M, Nicole A, Santiard-Baron D, Saillé C, Ceballos-Picot I. Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson's disease. Biochem Pharmacol 1998;56:645–55. [5] Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, et al. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 2006;84(3):647–54. [6] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20. [7] Cui Y, Xu X, Bi H, Zhu Q, Wu J, Xia X, et al. Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive o xygen species in diabetic retinopathy. Exp Eye Res 2006;83:807–16. [8] Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001;50:1938–42. [9] Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 2003;52:818–23. [10] Arnal E, Miranda M, Johnsen-Soriano S, Alvarez-Nölting R, Díaz-Llopis M, Araiz J, et al. Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Curr Eye Res 2009;34:928–38.
133
[11] Li ZG, Zhang W, Grunberger G, Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 2002;946:221–31. [12] Kowluru RA, Kern TS, Engerman RL, Armstrong D. Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants. Diabetes 1996;45:1233–7. [13] Haskins K, Bradley B, Powers K, Fadok V, Flores S, Ling X, et al. Oxidative stress in type 1 diabetes. Ann N Y Acad Sci 2003;1005:43–54. [14] Arnal E, Miranda M, Johnsen-Soriano S, Alvarez-Nölting R, Díaz-Llopis M, Araiz J, et al. Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Curr Eye Res 2009;34: 928–38. [15] Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid- interacting proteins, and neuronal function: breastmilk and fish are good for you. Annu Rev Cell Dev Biol 2005;21:633–57. [16] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fatty Acids 2007;77:251–61. [17] Innis SM. Dietary (n-3) fatty acids and brain development. J Nutr 2007;137:855–9. [18] Spector AA. Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. J Mol Neurosci 2001;16:159–65; discussion 215–221. [19] Scott BL, Bazan NG. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc Natl Acad Sci U S A 1989;86:2903–7. [20] Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 2005;115:2774–83. [21] Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L. Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 2006;10:59–73. [22] Kazantsev AG. Cellular pathways leading to neuronal dysfunction and degeneration. Drug News Perspect 2007;20:501–9. [23] Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Biophys Acta 2007;1768:1976–90. [24] Mukherjee PK, Chawla A, Loayza MS, Bazan NG. Docosanoids are multifunctional regulators of neural cell integrity and fate: significance in aging and disease. Prostaglandins Leukot Essent Fatty Acids 2007;77:233–8. [25] Lukiw WJ, Bazan NG. Survival signaling in Alzheimer's disease. Biochem Soc Trans 2006;34:1277–82. [26] Bazan NG. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res 2003;44:2221–33. [27] Brand A, Schonfeld E, Isharel I, Yavin E. Docosahexaenoic acid-dependent iron accumulation in oligodendroglia cells protects from hydrogen peroxide-induced damage. J Neurochem 2008;105:1325–35. [28] Uauy R, Dangour AD. Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev 2006;64:S24–33; discussion S72–91. [29] Sun GY, Xu J, Jensen MD, Simonyi A. Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 2004;45:205–13. [30] Birkle DL, Bazan NG. (19849. Effect of K+ depolarization on the synthesis of prostaglandins and hydroxyeicosatetra(5,8,11,14) enoic acids (HETE) in the rat retina. Evidence for esterification of 12-HETE in lipids. Biochim Biophys Acta 795, 564–573. [31] Reddy TS, Bazan NG. Long-chain acyl CoA synthetase in microsomes from rat brain gray matter and white matter. Neurochem Res 1985;10:377–86.
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[32] Reddy TS, Bazan NG. Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coenzyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain. J Neurosci Res 1985;13:381–90. [33] Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem 1998;273:13605–12. [34] Musiek ES, Brooks JD, Joo M, Brunoldi E, Porta A, Zanoni G, et al. Electrophilic cyclopentenone neuroprostanes are anti- inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem 2008;283:19927–35. [35] Diau GY, HsiehAT, Sarkadi-Nagy EA, Wijendran V, Nathanielsz PW, Brenna JT. The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system. BMC Med 2005;3:11. [36] Litman BJ, Niu SL, Polozova A, Mitchell DC. The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways: visual transduction. J Mol Neurosci 2001;16:237–42; discussion 79–84. [37] Salem N, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001;36:945–59. [38] Organisciak DT, Darrow RM, Jiang YL, Blanks JC. Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate. Invest Ophthalmol Vis Sci 1996;37:2243–57. [39] Kim HY, Akbar M, Lau A, Edsall L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J Biol Chem 2000;275:35215–23. [40] Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci U S A 1986;83:4021–5. [41] Weisinger HS, Armitage JA, Jeffrey BG, Mitchell DC, Moriguchi T, Sinclair AJ, et al. Retinal sensitivity loss in third-generation n-3 PUFA-deficient rats. Lipids 2002;37:759–65. [42] Bazan NG, Birkle DL, Reddy TS. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem Biophys Res Commun 1984;125:741–7. [43] Bazan NG. Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection. Prostaglandins Leukot Essent Fatty Acids 2009;81:205–11.
[44] Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, et al. Novel docosanoids inhibit brain ischemia-reperfusionmediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003;278:43807–17. [45] Mukherjee PK, Marcheselli VL, de Rivero Vaccari JC, Gordon WC, Jackson FE, Bazan NG. Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. Proc Natl Acad Sci U S A 2007;104:13158–63. [46] Mukherjee PK, Marcheselli VL, Barreiro S, Hu J, Bok D, Bazan NG. Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling. Proc Natl Acad Sci U S A 2007;104:13152–7. [47] Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 2004;101:8491–6. [48] Steele M, Stuchbury G, Münch G. The molecular basis of the prevention of Alzheimer's disease through healthy nutrition. Exp Gerontol 2007;42:28–36. [49] Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 2002;23:795–807. [50] Alvarez-Nölting R, Arnal E, Barcia JM, Miranda M, Romero FJ. Protection by DHA of early hippocampal changes in diabetes: possible role of CREB and NF-κB. Neurochem Res 2012;37:105–15. [51] Migliore L, Fontana I, Trippi F, Colognato R, Coppedè F, Tognoni G, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 2005;26:567–73. [52] Hossain MS, Hashimoto M, Gamoh S, Masumura S. Antioxidative effects of docosahexaenoic acid in the cerebrum versus cerebellum and brainstem of aged hypercholesterolemic rats. J Neurochem 1999;72:1133–8. [53] Arnal E, Miranda M, Barcia J, Bosch-Morell F, Romero FJ. Lutein and docosahexaenoic acid prevent cortex lipid peroxidation in streptozotocin-induced diabetic rat cerebral cortex. Neuroscience 2010;166(1):271–8. [54] Cao DH, Xu JF, Xue RH, Zheng WF, Liu ZL. Protective effect of chronic ethyl docosahexaenoate administration on brain injury in ischemic gerbils. Pharmacol Biochem Behav 2004;79:651–9. [55] Yavin E, Brand A, Green P. Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress. Nutr Neurosci 2002;5:149–57.
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The Anti-Oxidative Component of Docosahexaenoic Acid (DHA) in the Brain in Diabetes Emma Arnal*, María Miranda**, Siv Johnsen-Soriano*, Francisco J. Romero*, † *Fundación Oftalmológica del Mediterráneo, Valencia, Spain, **Universidad CEU Cardenal Herrera, Moncada, Spain, †Facultad de Medicina, Universidad Católica de Valencia ‘San Vicente Mártir’, Valencia, Spain
List of Abbreviations AA Arachidonic acid ALA Alfa-linolenic acid ARPE-19 Human retinal pigment epithelial cell line CNS Central nervous system COX Cyclooxygenase DHA Docosahexaenoic acid EPA Eicosapentanoic acid GSH Glutathione IL Interleukin LOX Lipoxygenase MCI Mild cognitive impairment NPD1 Neuroprotectin D1 PUFA Polyunsaturated fatty acid ROS Reactive oxygen species RPE Retinal pigment epithelium SOD Superoxide dismutase
INTRODUCTION: OXIDATIVE STRESS IN DIABETES Neuronal cells are particularly sensitive to oxidative insults, and reactive oxygen species (ROS) are involved in many neurodegenerative processes such as diabetes [1–3]. In these pathological conditions, cellular stress triggers mitochondrial oxidative damage, which may result in apoptosis and/or necrosis [4], and apoptosis induced by oxidative stress has been related to neurogenesis inhibition [5]. ROS generated by high glucose levels causes metabolic abnormalities which are involved in the development of
Diabetes: Oxidative Stress and Dietary Antioxidants. http://dx.doi.org/10.1016/B978-0-12-405885-9.00013-9
diabetes [6]. Previous studies have shown that oxidative stress is closely linked to apoptosis in a variety of cell types under hyperglycemic conditions [7]; furthermore apoptosis mediated by caspase-3 is activated in the brain of diabetic rats, and antioxidants are able to inhibit these activations [8–10] (Figure 13.1). Chronic degenerative brain disease in diabetes, known as 'diabetic encephalopathy', is a recognized complication that can occur in patients whose diabetes is long-standing. The mechanisms underlying diabetic encephalopathy are only partially understood, and can involve impairments in learning, memory, problem solving, and mental and motor speed (Figure 13.2) which are more common in type 1 diabetic patients than in the general population [11]. Neuronal cells are particularly sensitive to oxidative insults and ROS are involved in many neurodegenerative processes (not only diabetes but also Alzheimer's, Parkinson's, and Huntington's diseases, acute brain ischemia, and excitotoxicity) [1–3]. The possible source of oxidative stress in brain injury includes auto-oxidation of glucose, lipid peroxidation, decreased tissue concentrations of low molecular weight antioxidants such as reduced glutathione (GSH) (Figure 13.3) and impaired activities of antioxidant defense enzymes such as superoxide dismutase (SOD) and catalase [6,12,13]. Convincing evidence is now available from previous studies to prove the role of oxidative stress in the development of neuronal injury in the diabetic brain and the beneficial effects of antioxidants.
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13. THE ANTI-OXIDATIVE COMPONENT OF DOCOSAHEXAENOIC ACID (DHA) IN THE BRAIN IN DIABETES
FIGURE 13.1 Number of TUNEL-positive cells in the dentate gyrus of the hippocampus of diabetic and control rats. (*p < 0.05 vs. all groups). C, control; D, untreated diabetic rats; DI, diabetic rats treated with insulin.
FIGURE 13.2 Schematic representation of the potential impairments in diabetic encephalopathy.
However clinical trials testing the efficacy of antioxidants in the treatment of different diseases, including diabetes, have produced contradictory findings. This could be because most studies have focused on the use of antioxidants to block the production of ROS and other compounds, and perhaps it is too late to observe any beneficial effect and focus should be placed on blocking changes in intracellular signaling produced by oxidative stress. In this sense, many studies demonstrate the ability of antioxidant administration to revert the perjudicial effects of diabetes. The beneficial effect of lutein and DHA in diabetic animals and the way that these substances were able to ameliorate the oxidative stress present in diabetes have been studied [14].
DOCOSAHEXAENOIC ACID (DHA) DHA;4 22:6(n-3) (Figure 13.4); is a dietary essential (n-3) PUFA highly enriched in fish oils and concentrated up the food chain from photosynthetic and heterotrophic microalgae. In addition to these essential marine sources, DHA is also synthesized via the elongation and desaturation of the 20-carbon eicosapentanoic acid (EPA 20:5(n-3)), or by elongation of the 18-carbon (n-3) fatty acid, a-linolenic acid (ALA; 18:3 ( n-3)) enriched in flax (Linaceae), walnut (Juglandaceae), chia (Salvia hispanica), and other photosynthesizing terrestrial plants (Figure 13.5) [15–17]. In the brain, the glial and endothelial cells of the microvasculature, but not neurons, have some capacity to synthesize DHA from ALA and other (n-3) precursor fatty acids, but whether or not this contributes significantly to total brain DHA is not clear. The high concentration of DHA in the capillary endothelium suggests that DHA is taken up from the diet via
FIGURE 13.3 GSH concentration in the cortex and hippocampus of control and 4 or 12 weeks diabetic rats (*p < 0.05 vs. control 12 weeks groups). C, control; D, untreated diabetic rats.
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DHA and Oxidative Stress
FIGURE 13.4 DHA structure.
FIGURE 13.5 Eicosapentanoic acid and α-linolenic acid structures.
blood plasma DHA transporters including specific fatty-acid-binding lipoprotein carriers [17–19]. DHA is an absolute requirement for the development of the human central nervous system (CNS), and the continuous maintenance of brain cell function, illustrating the strong mechanistic link between an adequate supply of essential PUFA in the diet and the sustenance of cognitive health. During postnatal development, rapid accretion of DHA in the brain and retina takes place [16–18]. DHA attains its highest concentration in CNS synapses and in retinal photoreceptors; in fact, up to 60% of all fatty acids esterified in neuronal plasma membrane phospholipid consist of DHA. By means of a postnatal mouse development experimental model, it has been determined that dietary ALA is first taken up by the liver, where elongation and desaturation to DHA occurs, followed by its supply through the bloodstream to brain and retina, coinciding with photoreceptor development and synaptogenesis [17,19]. Brain and retinal cells therefore have a convenient and readily accessible supply of DHA that, through highly regulated, phospholipase-mediated exoprotease activities, liberates membrane-bound DHA to serve in neuroprotective and cell fate-signaling roles [20–26]. The beneficial neurophysiological actions of DHA occur in part through its direct maintenance of neuronal plasma membrane fluidity and functional integrity, and in part through the generation of docosanoids. The first identified DHA-derived mediator, neuroprotectin D1 (NPD1; MW 359), is formed through tandem phospholipase A2 (PLA2)-lipoxygenase (LOX) action on free DHA, via a 16,17S-DHA epoxide intermediate [20,24,27,28].
DHA AND OXIDATIVE STRESS DHA is most highly concentrated in photoreceptors, the nervous system, and testes, in descending order of concentration [26]. Both neurons and glia are richly endowed with this fatty acid. The outer segments of photoreceptors
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display the highest content of DHA in the human body. Moreover, DHA is present in much smaller quantities in non-nervous system cells. DHA is esterified at C2 of the glycerol backbone of phospholipids. In contrast the other major polyunsaturated fatty acyl group of cell phospholipids, the omega-6 family member arachidonic acid (AA), is distributed throughout the human body. Arachidonoyl chains of phospholipids are the reservoir of biologically active eicosanoids, and docosahexaenoyl chains of phospholipids are a reservoir for biologically active docosanoids. Both polyunsaturated fatty acids are also a target for free radical-mediated lipid peroxidation. Free (unesterified) AA and DHA are released from membrane phospholipids through the action of phospholipases in response to stimulation (e.g., neurotransmitters, cytokines, seizures, ischemia, neurotrauma, etc.) [26,29]. This response tells us that phospholipases are a regulatory gatekeeper in the initiation of the eicosanoid and docosanoid pathways under both physiological and pathological conditions. It remains to be determined whether any of the docosanoids are esterified back into phospholipids, which might, in turn, serve as reservoirs for readily-made bioactive mediators. In connection with this, there are examples of AA-derived lipoxygenation products incorporated into phospholipids of the nervous tissue [30]. During basal cell function, active ATP-dependent reacylation of AA and DHA takes place in membrane phospholipids [31,32]. Oxidative stress in the brain generates neuroprostanes from DHA through enzyme-independent reactions [33]. It has recently been shown that electrophilic cyclopentenone neuroprostanes elicit anti-inflammatory activity [34]. These compounds are formed from the peroxidation of DHA; therefore, it remains to be determined how the production of these compounds might be regulated and how they might exert specific actions such as antiinflammatory activity. DHA is required for brain and retina development [35] and has been implicated in several functions, including those of excitable membranes [36,37], memory [37], photoreceptor biogenesis and function [38], and neuroprotection [39]. One property the retina and brain share (insofar as omega-3 fatty acids are concerned) is their unusual ability to retain DHA even during prolonged dietary deprivation of essential fatty acids of the omega-3 family. To effectively reduce the DHA content in retinas and brains of rodents and non-human primates, dietary deprivation for more than one generation has been required [40,41]. This in turn produces impairments of retinal and brain function. Studies on DHA-mediated neuroprotection have prompted the following questions: Is the prosurvival action of DHA the result of replenishing the fatty acid into membrane phospholipids? Is it due to a more selective signaling by a DHA-derived mediator? Or is there a combination of mechanisms?
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This review highlights the elucidation of a specific DHA mediator that promotes the homeostatic regulation of cell integrity and retina and brain protection.
NEUROPROTECTIN D1 The retina forms mono-, di- and trihydroxy derivatives of DHA. Since lipoxygenase inhibitors block the formation of these derivatives, it was suggested that a lipoxygenase enzyme catalyzes their synthesis, and the name ‘docosanoids’ was introduced for the family of enzyme-derived products of DHA [42]. At the time of that study, the stereochemistry and bioactivity of these DHA-oxygenated derivatives were not defined. It was suggested, however, that these lipoxygenase-reaction products might be neuroprotective [42]. Upon the advent of mediator lipidomic analysis based on liquid chromatography, photodiode array, electrospray ionization, and tandem mass spectrometry (LC-MS/MS), Bazan and colleagues [43] identified oxygenation pathways for the synthesis of the stereospecific docosanoid NPD1 during brain ischemia-reperfusion [44], in human RPE cells [45–47], in human brain cells [20], and in the human brain. NPD1 synthesis occurs through DHA oxygenation by 15-lipoxygenase-1 (15-LOX-1). NPD1 then works through a stereospecific site, implying that this mediator acts in an autocrine fashion, and/or diffuses through the intercellular space (e.g., interphotoreceptor matrix to act in paracrine mode on nearby cells). One paracrine target in the retina could be photoreceptor cells and/or Müller cells. In addition, this group described the way that interleukin (IL)-1β, oxidative stress, or the Ca2+ ionophore A23187 activates the synthesis of NPD1 in ARPE19 cells (spontaneously transformed human RPE cells)
[45]. NPD1 in turn is a potent inhibitor of oxidativestress-induced apoptosis and of cytokine-mediated proinflammatory induction of cyclooxygenase 2 (COX-2). The name ‘neuroprotectin D1’ [47] was proposed, based on its neuroprotective bioactivity in oxidatively stressed RPE cells or brain and its potent ability to inactivate proapoptotic and pro-inflammatory signaling. ‘D1’ refers to this being the first identified neuroprotective mediator derived from DHA.
DHA AND OXIDATIVE STRESS IN THE BRAIN Oxidative stress results from an imbalance between the formation and the degradation of pro-oxidants or impaired cellular antioxidant mechanisms, and excessive oxidative stress leads to cell damage and apoptosis [48]. The brain is particularly susceptible to oxidative stress, because it has a high content of easily peroxidizable longchain PUFAs such as DHA and AA. Mitochondrial consumption of a large quantity of glucose to fuel the brain’s normal energy requirements also results in relatively high production of free radicals [49]. In diabetes, the oxidative stress situation increases the production of free radicals, resulting in increased lipid peroxidation in the brain [50]. Crucial oxidative damage has also been observed in subjects with mild cognitive impairment (MCI), suggesting an early role of oxidative stress [51]. Lipid peroxide levels are significantly lower in DHA-administered rats and reciprocally correlate with the DHA/AA ratio [52], indicating that dietary DHA contributes to the antioxidant defense, decreases oxidative stress, and protects against memory loss. This inference is consistent with the fact that DHA also increases the levels of antioxidant enzymes such as
FIGURE 13.6 Schematic representation of the potential DHA and NPD1 actions that may lead to apoptosis inhibition.
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DHA and Oxidative Stress in the Brain
catalase and glutathione peroxidase, and reduces glutathione levels with a concomitant decrease in the levels of ROS in the cortex and hippocampus of diabetes rat models [53]. Further, DHA has free radical-scavenging properties such as protection against lipid and protein peroxidation in developing and adult brains and attenuation of neuronal loss and cognitive and locomotor deficits in animal models of ischemia-reperfusion brain injury [54]. The antioxidant action of DHA in the brain has been underscored [55], despite the fact that its molecular structure contains six double bonds, which theoretically makes it a molecular target for peroxidation and sensitizes cells to ROS. Moreover, DHA can produce docosatrienes and resolvins, collectively known as docosanoids. In particular, NPD1 is formed through tandem phospholipase A2-lipoxygenase action on free DHA; it is a docosatriene that appears to be a major bioactive effector in neuronal tissues. Even a minute amount of NPD1 can promote anti-inflammatory and neuroprotective activity and inhibit oxidative stressinduced apoptosis [20] (Figure 13.6). These results suggest the notable role of DHA and/or DHA-derived mediators in the inhibition of oxidative stress.
References [1] Jackson GR, Werrbach-Perez K, Pan Z, Sampath D, Perez-Polo JR. Neurotrophin regulation of energy homeostasis in the central nervous system. Dev Neurosci 1994;16:285–90. [2] Dugan LL, Sensi SL, Canzoniero LM, Handran SD, Rothman SM, Lin TS, et al. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 1995;15:6377–88. [3] Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000;407:802–9. [4] Merad-Boudia M, Nicole A, Santiard-Baron D, Saillé C, Ceballos-Picot I. Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson's disease. Biochem Pharmacol 1998;56:645–55. [5] Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, et al. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res 2006;84(3):647–54. [6] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20. [7] Cui Y, Xu X, Bi H, Zhu Q, Wu J, Xia X, et al. Expression modification of uncoupling proteins and MnSOD in retinal endothelial cells and pericytes induced by high glucose: the role of reactive o xygen species in diabetic retinopathy. Exp Eye Res 2006;83:807–16. [8] Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 2001;50:1938–42. [9] Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 2003;52:818–23. [10] Arnal E, Miranda M, Johnsen-Soriano S, Alvarez-Nölting R, Díaz-Llopis M, Araiz J, et al. Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Curr Eye Res 2009;34:928–38.
133
[11] Li ZG, Zhang W, Grunberger G, Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 2002;946:221–31. [12] Kowluru RA, Kern TS, Engerman RL, Armstrong D. Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants. Diabetes 1996;45:1233–7. [13] Haskins K, Bradley B, Powers K, Fadok V, Flores S, Ling X, et al. Oxidative stress in type 1 diabetes. Ann N Y Acad Sci 2003;1005:43–54. [14] Arnal E, Miranda M, Johnsen-Soriano S, Alvarez-Nölting R, Díaz-Llopis M, Araiz J, et al. Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Curr Eye Res 2009;34: 928–38. [15] Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid- interacting proteins, and neuronal function: breastmilk and fish are good for you. Annu Rev Cell Dev Biol 2005;21:633–57. [16] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fatty Acids 2007;77:251–61. [17] Innis SM. Dietary (n-3) fatty acids and brain development. J Nutr 2007;137:855–9. [18] Spector AA. Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. J Mol Neurosci 2001;16:159–65; discussion 215–221. [19] Scott BL, Bazan NG. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc Natl Acad Sci U S A 1989;86:2903–7. [20] Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 2005;115:2774–83. [21] Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L. Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 2006;10:59–73. [22] Kazantsev AG. Cellular pathways leading to neuronal dysfunction and degeneration. Drug News Perspect 2007;20:501–9. [23] Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Biophys Acta 2007;1768:1976–90. [24] Mukherjee PK, Chawla A, Loayza MS, Bazan NG. Docosanoids are multifunctional regulators of neural cell integrity and fate: significance in aging and disease. Prostaglandins Leukot Essent Fatty Acids 2007;77:233–8. [25] Lukiw WJ, Bazan NG. Survival signaling in Alzheimer's disease. Biochem Soc Trans 2006;34:1277–82. [26] Bazan NG. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res 2003;44:2221–33. [27] Brand A, Schonfeld E, Isharel I, Yavin E. Docosahexaenoic acid-dependent iron accumulation in oligodendroglia cells protects from hydrogen peroxide-induced damage. J Neurochem 2008;105:1325–35. [28] Uauy R, Dangour AD. Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev 2006;64:S24–33; discussion S72–91. [29] Sun GY, Xu J, Jensen MD, Simonyi A. Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 2004;45:205–13. [30] Birkle DL, Bazan NG. (19849. Effect of K+ depolarization on the synthesis of prostaglandins and hydroxyeicosatetra(5,8,11,14) enoic acids (HETE) in the rat retina. Evidence for esterification of 12-HETE in lipids. Biochim Biophys Acta 795, 564–573. [31] Reddy TS, Bazan NG. Long-chain acyl CoA synthetase in microsomes from rat brain gray matter and white matter. Neurochem Res 1985;10:377–86.
II. ANTIOXIDANTS AND DIABETES
134
13. THE ANTI-OXIDATIVE COMPONENT OF DOCOSAHEXAENOIC ACID (DHA) IN THE BRAIN IN DIABETES
[32] Reddy TS, Bazan NG. Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coenzyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain. J Neurosci Res 1985;13:381–90. [33] Roberts LJ, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem 1998;273:13605–12. [34] Musiek ES, Brooks JD, Joo M, Brunoldi E, Porta A, Zanoni G, et al. Electrophilic cyclopentenone neuroprostanes are anti- inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem 2008;283:19927–35. [35] Diau GY, HsiehAT, Sarkadi-Nagy EA, Wijendran V, Nathanielsz PW, Brenna JT. The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system. BMC Med 2005;3:11. [36] Litman BJ, Niu SL, Polozova A, Mitchell DC. The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways: visual transduction. J Mol Neurosci 2001;16:237–42; discussion 79–84. [37] Salem N, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001;36:945–59. [38] Organisciak DT, Darrow RM, Jiang YL, Blanks JC. Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate. Invest Ophthalmol Vis Sci 1996;37:2243–57. [39] Kim HY, Akbar M, Lau A, Edsall L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J Biol Chem 2000;275:35215–23. [40] Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci U S A 1986;83:4021–5. [41] Weisinger HS, Armitage JA, Jeffrey BG, Mitchell DC, Moriguchi T, Sinclair AJ, et al. Retinal sensitivity loss in third-generation n-3 PUFA-deficient rats. Lipids 2002;37:759–65. [42] Bazan NG, Birkle DL, Reddy TS. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem Biophys Res Commun 1984;125:741–7. [43] Bazan NG. Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection. Prostaglandins Leukot Essent Fatty Acids 2009;81:205–11.
[44] Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, et al. Novel docosanoids inhibit brain ischemia-reperfusionmediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003;278:43807–17. [45] Mukherjee PK, Marcheselli VL, de Rivero Vaccari JC, Gordon WC, Jackson FE, Bazan NG. Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. Proc Natl Acad Sci U S A 2007;104:13158–63. [46] Mukherjee PK, Marcheselli VL, Barreiro S, Hu J, Bok D, Bazan NG. Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling. Proc Natl Acad Sci U S A 2007;104:13152–7. [47] Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 2004;101:8491–6. [48] Steele M, Stuchbury G, Münch G. The molecular basis of the prevention of Alzheimer's disease through healthy nutrition. Exp Gerontol 2007;42:28–36. [49] Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 2002;23:795–807. [50] Alvarez-Nölting R, Arnal E, Barcia JM, Miranda M, Romero FJ. Protection by DHA of early hippocampal changes in diabetes: possible role of CREB and NF-κB. Neurochem Res 2012;37:105–15. [51] Migliore L, Fontana I, Trippi F, Colognato R, Coppedè F, Tognoni G, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 2005;26:567–73. [52] Hossain MS, Hashimoto M, Gamoh S, Masumura S. Antioxidative effects of docosahexaenoic acid in the cerebrum versus cerebellum and brainstem of aged hypercholesterolemic rats. J Neurochem 1999;72:1133–8. [53] Arnal E, Miranda M, Barcia J, Bosch-Morell F, Romero FJ. Lutein and docosahexaenoic acid prevent cortex lipid peroxidation in streptozotocin-induced diabetic rat cerebral cortex. Neuroscience 2010;166(1):271–8. [54] Cao DH, Xu JF, Xue RH, Zheng WF, Liu ZL. Protective effect of chronic ethyl docosahexaenoate administration on brain injury in ischemic gerbils. Pharmacol Biochem Behav 2004;79:651–9. [55] Yavin E, Brand A, Green P. Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress. Nutr Neurosci 2002;5:149–57.
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