Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease

Docosahexaenoic acid (DHA), the main omega-3 fatty acid, is concentrated and avidly retained in membrane phospholipids of the nervous system. DHA is involved in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. Neuroprotectin D1 (NPD1), the first-identified stereoselective bioactive product of DHA, exerts neuroprotection in models of experimental stroke by down-regulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling, and infarct size. Moreover, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Photoreceptor membranes display the highest content of DHA of any cell. Retinal pigment epithelial cells participate in the phagocytosis of the tips of photoreceptor cells (photoreceptor outer segment renewal). There is a DHA retrieval-intercellular mechanism between both types of cells that conserves this fatty acid during this process. NPD1 promotes homeostatic regulation of the integrity of these two cells, particularly during oxidative stress, and this protective signaling may be relevant in retinal degenerative diseases. Moreover, neurotrophins are NPD1-synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer’s patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Aβ42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, anti-inflammatory, prosurvival repair signaling. Docosahexaenoic acid (DHA), the main omega-3 fatty acid, is concentrated and avidly retained in membrane phospholipids of the nervous system. DHA is involved in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. Neuroprotectin D1 (NPD1), the first-identified stereoselective bioactive product of DHA, exerts neuroprotection in models of experimental stroke by down-regulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling, and infarct size. Moreover, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Photoreceptor membranes display the highest content of DHA of any cell. Retinal pigment epithelial cells participate in the phagocytosis of the tips of photoreceptor cells (photoreceptor outer segment renewal). There is a DHA retrieval-intercellular mechanism between both types of cells that conserves this fatty acid during this process. NPD1 promotes homeostatic regulation of the integrity of these two cells, particularly during oxidative stress, and this protective signaling may be relevant in retinal degenerative diseases. Moreover, neurotrophins are NPD1-synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer’s patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Aβ42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, anti-inflammatory, prosurvival repair signaling. Cell function and integrity is sustained in the central nervous system (CNS) by complex intra- and intercellular signaling networks driven by modulators such as synaptic activity, neurotrophins, and gene programs. The molecular organization and functions of cellular membranes are pivotal in cell signaling. Docosahexaenoic acid (DHA), the main omega-3 fatty acid, is concentrated in membrane phospholipids of the CNS. Remarkably, DHA is avidly retained in the CNS. Prolonged periods of dietary deprivation are required to decrease DHA tissue content, which results in functional impairments (1SanGiovanni J.P. Chew E.Y. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.Prog. Retin. Eye Res. 2005; 24: 87-138Crossref PubMed Scopus (626) Google Scholar, 2Neuringer 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: 517-541Crossref PubMed Scopus (672) Google Scholar). These changes are restored by selective refeeding of omega-3 fatty acids. DHA is implicated in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. The discovery of neuroprotectin D1 (NPD1), the first identified bioactive derivative of DHA, has allowed for fundamental questions to be directly addressed concerning the biology of omega-3 fatty acids and DHA action mechanisms in experimental stroke and neurodegenerations. This review highlights NPD1's cell-protective, anti-inflammatory, prosurvival repair signaling. To isolate and quantify unesterified (free) DHA and arachidonic acid in the CNS, we developed gradient-thickness thin-layer chromatography, which was reported in this journal (3Bazan Jr., N.G. Joel C.D. Gradient-thickness thin-layer chromatography for the isolation and analysis of trace amounts of free fatty acids in large lipid samples.J. Lipid Res. 1970; 11: 42-47Abstract Full Text PDF PubMed Google Scholar). Using this approach, it was found that the unesterified (free) DHA pool increases during brain ischemia and intense synaptic activity, such as seizures, as a result of phospholipase A2 (PLA2) action. Although the CNS contains phospholipids richly endowed with docosahexaenoyl fatty acyl-chains, it displays an undetectable quantity of unesterified (free) DHA under basal, unstimulated conditions. This means that production of unesterified (free) DHA is tightly controlled by a PLA2, by its removal (e.g., by reacylation) and by peroxidation. Free DHA that is incorporated into membrane phospholipids first becomes the substrate of docosahexaenoyl-CoA synthethase for its channeling through acyltransferases, which incorporate this fatty acid into phospholipids (4Bazan N.G. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor.J. Lipid Res. 2003; 44: 2221-2233Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 5Horrocks L.A. Farooqui A.A. NMDA receptor-stimulated release of arachidonic acid: mechanisms for the Bazan effect. In Cell Signal Transduction, Second Messengers, and Protein Phosphorylation in Health and Disease. A. M. Municio and M. T. Miras-Portugal. Plenum Press, New York, NY1994: 113-128Google Scholar, 6Sun G.Y. Xu J. Jensen M.D. Simonyi A. Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases.J. Lipid Res. 2004; 45: 205-213Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar). During mouse brain ischemia reperfusion (BIR), NPD1 synthesis increases up to 8 h. To test the hypothesis that this rise reflects an endogenous protective response, NPD1 was administered directly into the cerebral ventricles and was found to counteract polymorphonuclear neutrophil infiltration, proinflammatory gene signaling, and infarct size (7Marcheselli V.L. Hong S. Lukiw W.J. Tian X.H. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. al et Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar). Likewise, continuous infusion of DHA into the ventricles during the initial 2 days of reperfusion inhibited polymorphonuclear neutrophil infiltration into the hippocampus and the neocortex. BIR-induced increases in NF-κB binding and up-regulation of cyclooxygenase-2 (COX-2) expression was also attenuated by DHA or NPD1 infusion. These results were mirrored by cultured human neural progenitor cells treated with the proinflammatory cytokine, interleukin-1β (IL-1β). NPD1’s bioactivity is underscored by its ability to reduce the infarct volume by approximately half (7Marcheselli V.L. Hong S. Lukiw W.J. Tian X.H. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. al et Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar). To explore potential translational application of these findings, DHA was infused intravenously after 2 h of brain ischemia produced by transient occlusion of the right middle cerebral artery. As a result, neurobiological recovery was remarkably improved, brain damage was reduced, and NPD1 content was bolstered in the right side of the brain, implying that systemically administered DHA was taken up from the bloodstream by the brain and used for NPD1 synthesis. In turn, NPD1 exerted neuroprotection (8Belayev L. Marcheselli V.L. Khoutorova L. Turco E.B. Rodriguez de Busto R. Ginsberg M.D. Bazan N.G. DHA complexed to albumin elicits high-grade ischemic neuroprotection.Stroke. 2005; 36: 118-123Crossref PubMed Scopus (118) Google Scholar). Thus, if a brain injury is below a certain threshold, endogenous synthesis of NPD1 may be able to cope with damage initiation and prevent its progression. However, if the injury surpasses a certain threshold, NPD1 synthesis and its ability to elicit protection are overwhelmed. The name “neuroprotectin D1” was suggested based upon its neuroprotective bioactivity in BIR and oxidatively stressed retinal pigment epithelial (RPE) cells, as well as its potent ability to inactivate proapoptotic and proinflammatory signaling. “D1” refers to it being the first identified mediator derived from DHA (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar). RPE cells, the most active phagocytes of the body, support photoreceptor cells by participating in the daily shedding, internalization, and degradation (phagocytosis) of photoreceptor outer segments (membrane discs) tips (Fig. 1). The photoreceptors and RPE are constantly subjected to environmental and intrinsic factors that potentially disrupt homeostasis: high oxygen tension, intense light during the day, and cell membranes with high content of polyunsaturated fatty acyl chains in their phospholipids (DHA and also 20:4,n-6-arachidonic acid). In models of retinal degeneration, lipid peroxidation, a potentially cell-damaging event, does occur in outer-segment discs (10Organisciak D.T. Darrow R.M. Jiang Y.L. Blanks J.C. Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate.Invest. Ophthalmol. Vis. Sci. 1996; 37: 2243-2257PubMed Google Scholar). Moreover, in drusen (deposits of debris-like material that accumulate between the RPE cells and Bruch’s membrane) from patients with age-related macular degeneration, DHA oxidation products can form protein adducts (11Crabb J.W. Miyagi M. Gu X. Shadrach K. West K.A. Sakaguchi H. Kamei M. Hasan A. Yan L. Rayborn M.E. al et Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.Proc. Natl. Acad. Sci. USA. 2002; 99: 14682-14687Crossref PubMed Scopus (1000) Google Scholar). RPE cells have developed endogenous mechanisms to cope with these challenges and guard against damage, such as the presence of antioxidants (e.g., Vitamin E), which contribute to preserving cellular integrity. RPE cells respond to oxidative stress by activating the NPD1 synthesis (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar). Previous studies have shown that the retina forms mono-, di-, and trihydroxy derivatives of DHA, and that lipoxygenase inhibitors block this synthesis, suggesting an enzymatic process of a lipoxygenase nature (12Bazan N.G. Birkle D.L. Reddy T.S. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina.Biochem. Biophys. Res. Commun. 1984; 125: 741-747Crossref PubMed Scopus (95) Google Scholar). At the time these lipoxygenase products were found, the stereochemistry and bioactivity of these DHA-oxygenated derivatives were not defined. It was proposed that these lipoxygenase products might be neuroprotective (and at the same time, the name “docosanoids” was suggested) (12Bazan N.G. Birkle D.L. Reddy T.S. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina.Biochem. Biophys. Res. Commun. 1984; 125: 741-747Crossref PubMed Scopus (95) Google Scholar). Upon the advent of mediator lipidomics, oxygenation pathways were identified for the synthesis of the docosanoid NPD1 during BIR (7Marcheselli V.L. Hong S. Lukiw W.J. Tian X.H. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. al et Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar) and in RPE cells (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar). NPD1 is formed from free (unesterified) DHA and released from membrane phospholipids by a PLA2. 15-Lipoxygenase-1, IL-1β, oxidative stress, or the Ca2+ ionophore A23187 activates the synthesis of NPD1 (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar), and, in turn, this lipid mediator acts in an autocrine fashion to act in a paracrine mode on photoreceptor cells and/or Mu¨ller cells (13Bazan N.G. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors.Trends Neurosci. 2006; 29: 263-271Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 14Bazan N.G. Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture.Invest. Ophthalmol. Vis. Sci. 2007; PubMed Scopus Google Scholar). The CNS displays an ability to DHA during periods of omega-3 fatty acid deprivation (1SanGiovanni J.P. Chew E.Y. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.Prog. Retin. Eye Res. 2005; 24: 87-138Crossref PubMed Scopus (626) Google Scholar, N.G. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors.Trends Neurosci. 2006; 29: 263-271Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, M. docosahexaenoic acid levels in rod outer segments of rats with and Vis. 2002; 8: Google Scholar). In photoreceptor and in mouse the omega-3 that dietary acid is and in the its through the to the retina and brain Bazan N.G. is to the brain and retina by the Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). intercellular the of DHA N. and Rodriguez de in and DHA in In Retinal and of an in S. N. N. and M. Scholar). The up DHA and acid from the and and acid to DHA is into as de Turco E.B. Bazan N.G. in lipid in retinal pigment epithelial cells at the of and phagocytosis of photoreceptor Eye Res. PubMed Scopus Google Scholar), and to the brain through the brain and to the RPE or retina through the or DHA is is a mechanism It is that with phospholipids DHA to the RPE and brain, and to a the and Thus, is a DHA by the CNS. The intercellular DHA the the to the RPE cells and the is shown in The DHA from the RPE to the photoreceptor outer segment via the DHA in the RPE by the or taken up during from the of the photoreceptor and through the to the segment phospholipids are DHA to the outer segment through the for of RPE cells which in is released and, in an autocrine elicits its action through a It has shown that bloodstream of DHA and that these cells are with at (13Bazan N.G. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors.Trends Neurosci. 2006; 29: 263-271Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). It is that brain DHA mechanisms may Photoreceptor outer segment phagocytosis by the RPE cells results in a daily of phospholipids in The DHA and omega-3 fatty acids are by the segment of the photoreceptor through the the of (DHA of in photoreceptors (Fig. 1). omega-3 fatty acids are also of photoreceptor outer an omega-3 fatty acid be not the this The of photoreceptors DHA as the molecular outer segment which are by RPE cells in a and fashion in M. J. K.A. S. Bazan N.G. of A2 in the human in phagocytosis of photoreceptor outer Ophthalmol. Vis. Sci. 2007; PubMed Scopus Google Scholar). The of the outer segments as a of the of outer segment membrane in to the phagocytosis of the tips at an During photoreceptor outer segment and are In DHA and from the of rod photoreceptor outer segments are from the RPE to segments through the To the potential significance of NPD1 in retinal neurotrophins, which are in photoreceptor synthesis and release of NPD1 from RPE derived a of the is the most potent of NPD1 synthesis J. a Rev. Neurosci. 2003; PubMed Scopus Google Scholar). elicit increases in NPD1 release on the side of the RPE cell P.K. Marcheselli V.L. S. J. Bazan N.G. retinal pigment epithelial cell survival through neuroprotectin D1 Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar). This side of the cell the photoreceptor cells (Fig. 1). NPD1 may be in retinal of photoreceptor cells is the of retinal degenerative diseases. In of and age-related macular of in photoreceptors Retinal cell signaling pathways and of and and stress are and function is and of retinal an RPE cells the photoreceptor cells T.S. M. J. in result in of the a of the human disease 2004; PubMed Scopus Google Scholar). of retinal in by photoreceptor cell In forms of J.C. Anderson synthesis of DHA in patients with Lipid Res. Full Text Full Text PDF PubMed Google Scholar, Anderson Anderson fatty acids are in of not Ophthalmol. Vis. Sci. Google Scholar) and in N.G. Reddy T.S. content of and in phospholipids in Biophys. Res. Commun. PubMed Scopus Google Scholar, P.K. Marcheselli V.L. J.C. de Bazan N.G. Photoreceptor outer segment phagocytosis oxidative with neuroprotectin D1 Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar), a decrease of DHA content in of these is that DHA to the retina may photoreceptor function by the of DHA to However, the between decreased DHA in the and disease initiation and to human display decreased amounts of DHA in photoreceptors M. docosahexaenoic acid levels in rod outer segments of rats with and Vis. 2002; 8: Google Scholar). This a retinal to stress the of the of lipid to the protection of photoreceptors M. docosahexaenoic acid levels in rod outer segments of rats with and Vis. 2002; 8: Google Scholar). In in retinal degeneration, is of DHA from in light are from such and degeneration, suggesting that is and/or a NPD1 signaling may be as a in DHA is with W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar) and has also in Alzheimer’s disease gene expression in human brain cells in after to DHA, and that proinflammatory and the proinflammatory J. Bazan N.G. Lukiw W.J. expression of in and and up-regulation of and pro-inflammatory Neurosci. Res. 2002; PubMed Scopus Google Scholar), and expression are by Aβ42 and by DHA or The expression of these proinflammatory is in the of patients J. Bazan N.G. Lukiw W.J. expression of in and and up-regulation of and pro-inflammatory Neurosci. Res. 2002; PubMed Scopus Google Scholar). Overall, Aβ42 a complex proapoptotic gene-expression that the proapoptotic and that participate in signaling in DHA and NPD1 expression of and antiapoptotic of the gene and of and and are in cells cells and not with DHA or The antiapoptotic are by DHA and and the highest significance of any gene in human neural cells W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). of DHA from NPD1 an which are or W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). To explore the significance of the levels of this lipid mediator were in CA1 an of the brain involved in and by in of to the and brain were from patients at a of disease development W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). DHA pool in were in and NPD1 levels in were approximately of in W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). on brain region and of disease the of in brain has to from to to of for the same Thus, the of of is to for the in the NPD1 content in These decreased of unesterified DHA, NPD1 levels are in As a result, NPD1’s neuroprotective bioactivity during brain cell may be In the same human CA1 was was decreased of NPD1 in CA1 may be at in by a in the expression and regulation of the and/or for NPD1 W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). analysis has allowed for initiation of CNS omega-3 fatty by the discovery of NPD1 in the CNS (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar), the of its and of of the biology of and cell NPD1 promotes CNS cell through of signaling and it the expression of proinflammatory (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar). in as well as in neural progenitor cells by IL-1β, NPD1 inhibits induction (7Marcheselli V.L. Hong S. Lukiw W.J. Tian X.H. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. al et Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar, P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar). In NPD1 infarct size and inhibits polymorphonuclear leukocyte infiltration (7Marcheselli V.L. Hong S. Lukiw W.J. Tian X.H. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. al et Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar). Moreover, in human brain progenitor cells in W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar), proinflammatory by NPD1 are IL-1β, and proinflammatory NPD1 bioactivity as a that proinflammatory injury to the a in which signaling is in the form of age-related macular degeneration, and in which in oxidative stress on signaling pathways in the CNS in turn, participate in the of degenerative disease and to cell damage and, cell The of the initiation and of of (1SanGiovanni J.P. Chew E.Y. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.Prog. Retin. Eye Res. 2005; 24: 87-138Crossref PubMed Scopus (626) Google Scholar). NPD1 is formed in to oxidative stress and, in to of proinflammatory protein expression to counteract oxidative stress (9Mukherjee P.K. Marcheselli V.L. Serhan C.N. Bazan N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 8491-8496Crossref PubMed Scopus (655) Google Scholar, W.J. Marcheselli V.L. M. A. K. Serhan C.N. Bazan N.G. role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and 2005; PubMed Scopus Google Scholar). NPD1 synthesis in an to the injury and/or proinflammatory and to P.K. Marcheselli V.L. S. J. Bazan N.G. retinal pigment epithelial cell survival through neuroprotectin D1 Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar). The presence of bioactive docosanoids in the CNS, and the of the and involved in docosanoid synthesis, to be of NPD1 pathways into the NPD1 signaling pathways by this lipid Overall, selective to the CNS be and NPD1 and its cellular might the of to cell and, in turn, survival in and retinal The experimental of the of NPD1 to or the initiation and of neurodegenerative is a with the of these into the