title: Omega-3 essential fatty acids modulate initiation and progression of neurodegenerative disease.
abstract: The significance of the selective enrichment in omega-3 essential fatty acids in photoreceptors and synaptic membranes of the nervous system has remained, until recently, incompletely understood. While studying mechanisms of cell survival in neural degeneration, we discovered a docosanoid synthesized from unesterified docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). This lipid mediator is a docosanoid because it is derived from the 22 carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20 carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We discovered that NPD1 is promptly made in response to oxidative stress, as a response to brain ischemia-reperfusion, and in the presence of neurotrophins. NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed retinal pigment epithelial (RPE) cells, and in human brain cells exposed to amyloid-beta (Abeta) peptides. We thus envision NPD1 as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by imbalances in normal neural function. We provide here, in three sections, recent experimental examples that highlight the specificity and potency of NPD1 spanning beneficial bioactivity during initiation and early progression of neurodegeneration: (1) during retinal signal phototransduction, (2) during brain ischemia-reperfusion, and (3) in Alzheimer's disease (AD) and stressed human brain cell models of AD. From this experimental evidence, we conclude that DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.
authors.affiliation: Diater Laboratorios, 28918, Leganes, Madrid, Spain. r.palacios@diater.com
authors.forename: R
authors.initials: R
authors.lastname: Palacios-Pelaez
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Lukiw
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology; D055537:Light Signal Transduction / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology
chemical_list: D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D018696:Neuroprotective Agents; C487679:protectin D1; D004281:Docosahexaenoic Acids
references.citation: J Alzheimers Dis. 2010;19(1):341-53
references.pmid: 20061649
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):287-93
references.pmid: 18037281
references.citation: J Immunol. 2004 Mar 1;172(5):2731-8
references.pmid: 14978070
references.citation: Ophthalmic Res. 2001 Jul-Aug;33(4):191-5
references.pmid: 11464070
references.citation: Proc Natl Acad Sci U S A. 1989 Apr;86(8):2903-7
references.pmid: 2523075
references.citation: J Nutr. 2010 Apr;140(4):848-53
references.pmid: 20181791
references.citation: Nutr Neurosci. 2008 Apr;11(2):75-83
references.pmid: 18510807
references.citation: Behav Neurol. 2009;21(1):117-28
references.pmid: 19847050
references.citation: Am J Pathol. 2005 May;166(5):1283-9
references.pmid: 15855630
references.citation: Stroke. 2009 Sep;40(9):3121-6
references.pmid: 19542051
references.citation: J Biol Chem. 2008 Nov 14;283(46):31315-22
references.pmid: 18801740
references.citation: J Neurosci Res. 1999 Aug 15;57(4):479-86
references.pmid: 10440897
references.citation: Acta Neuropathol. 2009 Jul;118(1):103-13
references.pmid: 19319544
references.citation: Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):136-41
references.pmid: 17285000
references.citation: Trends Neurosci. 2006 May;29(5):263-71
references.pmid: 16580739
references.citation: J Nutr. 2010 Apr;140(4):858-63
references.pmid: 20181788
references.citation: J Alzheimers Dis. 2006 Sep;10(1):59-73
references.pmid: 16988483
references.citation: Neurochem Res. 2004 Jun;29(6):1287-97
references.pmid: 15176485
references.citation: Am J Ophthalmol. 2009 Jul;148(1):83-9.e1
references.pmid: 19327745
references.citation: World Rev Nutr Diet. 2009;99:55-70
references.pmid: 19136839
references.citation: J Clin Invest. 2005 Oct;115(10):2774-83
references.pmid: 16151530
references.citation: Exp Neurol. 2010 Jan;221(1):18-25
references.pmid: 19747481
references.citation: J Am Geriatr Soc. 1977 May;25(5):220-9
references.pmid: 856907
references.citation: J Mol Neurosci. 2001 Apr-Jun;16(2-3):159-65; discussion 215-21
references.pmid: 11478370
references.citation: Mol Neurobiol. 2010 Aug;42(1):10-6
references.pmid: 20414817
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13158-63
references.pmid: 17670935
references.citation: J Alzheimers Dis. 2010;19(2):489-502
references.pmid: 20110596
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):205-11
references.pmid: 19520558
references.citation: Mol Vis. 2009 Jun 13;15:1185-93
references.pmid: 19536303
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):251-61
references.pmid: 18060754
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):233-8
references.pmid: 18060755
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):213-21
references.pmid: 19523795
references.citation: N Engl J Med. 2010 Jan 28;362(4):329-44
references.pmid: 20107219
references.citation: Invest Ophthalmol Vis Sci. 2007 Nov;48(11):4866-81; biography 4864-5
references.pmid: 17962433
references.citation: J Nutr. 2007 Apr;137(4):855-9
references.pmid: 17374644
references.citation: Br J Ophthalmol. 2009 Sep;93(9):1241-6
references.pmid: 19508997
references.citation: J Alzheimers Dis. 2010;21(1):1-14
references.pmid: 20182045
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S400-5
references.pmid: 19018037
references.citation: Curr Pharm Des. 2009;15(36):4186-90
references.pmid: 20041820
references.citation: Neuroscience. 1999;94(1):305-14
references.pmid: 10613520
references.citation: Biochim Biophys Acta. 2007 Aug;1768(8):1976-90
references.pmid: 17433250
references.citation: Ann N Y Acad Sci. 2005 Aug;1053:137-47
references.pmid: 16179516
references.citation: Drug News Perspect. 2007 Oct;20(8):501-9
references.pmid: 18080037
references.citation: Curr Opin Clin Nutr Metab Care. 2010 Jan;13(1):28-33
references.pmid: 19841580
references.citation: Indian J Pediatr. 2005 Mar;72(3):239-42
references.pmid: 15812120
references.citation: Neuropharmacology. 2010 Sep-Oct;59(4-5):243-67
references.pmid: 20167227
references.citation: Mol Cell Biochem. 1992 Oct 21;116(1-2):19-25
references.pmid: 1480148
references.citation: Insight. 2008 Oct-Dec;33(4):20-5; quiz 26-7
references.pmid: 19227095
references.citation: Mol Neurobiol. 2006 Dec;34(3):181-92
references.pmid: 17308351
references.citation: J Neurosci Res. 1998 Sep 1;53(5):583-92
references.pmid: 9726429
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):924-9
references.pmid: 20176130
references.citation: J Neurochem. 1998 Jun;70(6):2484-91
references.pmid: 9603213
references.citation: Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):85-9
references.pmid: 19804838
references.citation: Gerontology. 2010;56(1):3-14
references.pmid: 19752507
references.citation: J Med Food. 2007 Jun;10(2):225-31
references.pmid: 17651056
references.citation: J Neurosci Res. 2002 Nov 1;70(3):462-73
references.pmid: 12391607
references.citation: Biochem Soc Trans. 2006 Dec;34(Pt 6):1277-82
references.pmid: 17073801
references.citation: J Biol Chem. 2003 Oct 31;278(44):43807-17
references.pmid: 12923200
references.citation: Blood Press. 1995 May;4(3):177-86
references.pmid: 7670652
references.citation: Annu Rev Cell Dev Biol. 2005;21:633-57
references.pmid: 16212510
references.citation: J Invest Surg. 2005 Nov-Dec;18(6):335-50
references.pmid: 16319055
references.citation: J Nutr. 2010 Apr;140(4):869-74
references.pmid: 20181786