Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina

Bazán, Nicolás G.; Birkle, Dale L.; Reddy, T. Sanjeeva

doi:10.1016/0006-291x(84)90601-6

Cited by 98 publications

(54 citation statements)

References 20 publications

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“…A correction of the trout gill work indicated that the DHA products were not prostaglandins but rather LO products (84). Aveldano and Sprecher (85) observed that platelet LO produced a monohydroxylated form of DHA, and Bazan et al (86) found a similar product after incubations with rat retinas. However, Kim and co-workers (80,81) demonstrated that the brain DHA products were a racemic mixture and thus unlikely to be enzymatic products.…”

Section: Mechanisms Of Action Of Dhamentioning

confidence: 93%

Mechanisms of action of docosahexaenoic acid in the nervous system

Salem

Litman

Kim

et al. 2001

Lipids

825

508

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This review describes (from both the animal and human literature) the biological consequences of losses in nervous system docosahexaenoate (DHA). It then concentrates on biological mechanisms that may serve to explain changes in brain and retinal function. Brief consideration is given to actions of DHA as a nonesterified fatty acid and as a docosanoid or other bioactive molecule. The role of DHA-phospholipids in regulating G-protein signaling is presented in the context of studies with rhodopsin. It is clear that the visual pigment responds to the degree of unsaturation of the membrane lipids. At the cell biological level, DHA is shown to have a protective role in a cell culture model of apoptosis in relation to its effects in increasing cellular phosphatidylserine (PS); also, the loss of DHA leads to a loss in PS. Thus, through its effects on PS, DHA may play an important role in the regulation of cell signaling and in cell proliferation. Finally, progress has been made recently in nuclear magnetic resonance studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation.Paper no. L8776 in Lipids 36, 945-959 (September 2001)

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Section: Mechanisms Of Action Of Dhamentioning

confidence: 93%

Mechanisms of action of docosahexaenoic acid in the nervous system

Salem

Litman

Kim

et al. 2001

Lipids

825

508

View full text Add to dashboard Cite

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“…These findings suggest that an unrecognized function of photoreceptor phagocytosis is to induce NPD1 synthesis and thereby elicit cytoprotection. The RPE is highly susceptible to oxidative stress because of the high oxygen consumption of the retina, active f lux of polyunsaturated fatty acid (DHA)-containing phospholipids, and exposure to light (2,33). Thus, NPD1 may be a major endogenous promoter of RPE cell survival during POS renewal.…”

Section: Pos Phagocytosis Selectively Attenuates Oxidative Stress-indmentioning

confidence: 99%

“…These observations support the notion that as free DHA accumulates in the ARPE-19 cells during POS phagocytosis, it is a substrate for NPD1 synthesis. At the time of the initial identification of lipoxygenase products from DHA, mono-, di-, and trihydroxylated derivatives were identified (33). Further studies are needed to determine whether other docosanoids may also be formed under these conditions.…”

Section: Pos Phagocytosis Selectively Attenuates Oxidative Stress-indmentioning

confidence: 99%

Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis

Mukherjee

Marcheselli

Vaccari

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

100

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Photoreceptor cell (rods and cones) renewal is accompanied by intermittent shedding of the distal tips of the outer segment followed by their phagocytosis in the retinal pigment epithelial (RPE) cells. This renewal is essential for vision, and it is thought that it fosters survival of photoreceptors and of RPE cells. However, no specific survival messenger/mediators have as yet been identified. We show here that photoreceptor outer segment (POS) phagocytosis markedly attenuates oxidative stress-induced apoptosis in ARPE-19 cells in culture. This phenomenon does not seem to be a generalized outcome of phagocytosis because nonbiological (polystyrene microsphere) phagocytosis did not elicit protection. The free docosahexaenoic acid (DHA) pool size and neuroprotectin D1 (NPD1) content increased during POS phagocytosis but not during microspheres phagocytosis. We have also explored other lipid mediators [lipoxin A4 and 15(S)-and 12(S)-hydroxyeicosatetraenoic acids] under these conditions and found them unchanged upon POS phagocytosis. Moreover, oxidative stress challenge to RPE cells undergoing POS phagocytosis further increased DHA and NPD1 content. Under these conditions, NPD1 was found within the RPE cells as well as in the culture medium, suggesting autocrine and paracrine bioactivity. Furthermore, using deuterium-labeled DHA, we show that as the availability of free DHA increases during oxidative stress, NPD1 synthesis is augmented in ARPE-19 cells. Our data suggest a distinct signaling that promotes survival of photoreceptor and RPE cells by enhancing the synthesis of NPD1 during phagocytosis. Taken together, NPD1 may be a mediator that promotes homeostatic regulation of cell integrity during photoreceptor cell renewal. docosahexaenoic acid ͉ polystyrene microspheres ͉ retinal pigment epithelial cells ͉ survival ͉ omega-3 fatty acids

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Section: Introductionmentioning

confidence: 95%

“…Although it has been reported that DHA participates in retina and brain damage [1][2][3][4][5], our laboratory, in contrast, showed that the retina forms mono-, di-and trihydroxyl derivatives of DHA that may be neuroprotective [6]. Since lipoxygenase inhibitors were found to block this synthesis, an enzymatic process catalyzed by a lipoxygenase was implied [6] and the name "docosanoids" was suggested because they are derived from the 22C DHA. Upon the development of lipidomic analysis based on liquid chromatography, photodiode array, electrospray ionization, and tandem mass spectrometry (LC-PDA-ESI-MS-MS-based lipidomic analysis), a collaboration between the group of Charles Serhan (Harvard Medical School, http://hms.harvard.edu/hms/home.asp) and our group identified oxygenation pathways for the synthesis of the docosanoid neuroprotectin D1 (NPD1) and its bioactivity during brain ischemia-reperfusion [7] and in retinal pigment epithelial (RPE) cells challenged by oxidative stress [8].…”

Section: Introductionmentioning

confidence: 95%

Docosanoids are multifunctional regulators of neural cell integrity and fate: Significance in aging and disease

Mukherjee

Chawla

Loayza

et al. 2007

Prostaglandins, Leukotrienes and Essential Fatty Acids

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The identification of neuroprotectin D1 (NPD1), a biosynthetic product of docosahexaenoic acid (DHA), in brain and retina as well as the characterization of its bioactivity, is generating a renewed interest in the functional role and pathophysiological significance of omega-3 fatty acids in the central nervous system.Neurotrophins, particularly pigment epithelium-derived factor (PEDF), induce NPD1 synthesis and its polarized apical secretion, implying paracrine and autocrine bioactivity of this lipid mediator. Also, DHA and PEDF synergistically activate NPD1 synthesis and antiapoptotic protein expression and decreased proapoptotic Bcl-2 protein expression and caspase 3 activation during oxidative stress.In experimental stroke, endogenous NPD1 synthesis was found to be upregulated, and the infusion of the lipid mediator into the brain under these conditions revealed neuroprotective bioactivity of NPD1.The hippocampal CA1 region from Alzheimer's disease (AD) patients (rapidly sampled) shows a major reduction in NPD1.The interplay of DHA-derived neuroprotective signaling aims to counteract proinflammatory, celldamaging events triggered by multiple, converging cytokine and amyloid peptide factors, as in the case of AD. Generation of NPD1 from DHA thereby appears to redirect cellular fate toward successful preservation of retinal pigment epithelial (RPE)-photoreceptor cell integrity and brain cell aging. The Bcl-2 pro-and antiapoptotic proteins, neurotrophins, and NPD1, lie along a cell fateregulatory pathway whose component members are highly interactive, and have potential to function cooperatively in cell survival. Agents that stimulate NPD1 biosynthesis, NPD1 analogs, or dietary regimens may be useful as new preventive/therapeutic strategies for neurodegenerative diseases.

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Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina

Cited by 98 publications

References 20 publications

Mechanisms of action of docosahexaenoic acid in the nervous system

Mechanisms of action of docosahexaenoic acid in the nervous system

Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis

Docosanoids are multifunctional regulators of neural cell integrity and fate: Significance in aging and disease

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