title: Pretreatment with pyridoxamine mitigates isolevuglandin-associated retinal effects in mice exposed to bright light.
abstract: The benefits of antioxidant therapy for treating age-related macular degeneration, a devastating retinal disease, are limited. Perhaps species other than reactive oxygen intermediates should be considered as therapeutic targets. These could be lipid peroxidation products, including isolevuglandins (isoLGs), prototypical and extraordinarily reactive γ-ketoaldehydes that avidly bind to proteins, phospholipids, and DNA and modulate the properties of these biomolecules. We found isoLG adducts in aged human retina but not in the retina of mice kept under dim lighting. Hence, to test whether scavenging of isoLGs could complement or supplant antioxidant therapy, we exposed mice to bright light and found that this insult leads to retinal isoLG-adduct formation. We then pretreated mice with pyridoxamine, a B6 vitamer and efficient scavenger of γ-ketoaldehydes, and found that the levels of retinal isoLG adducts are decreased, and morphological changes in photoreceptor mitochondria are not as pronounced as in untreated animals. Our study demonstrates that preventing the damage to biomolecules by lipid peroxidation products, a novel concept in vision research, is a viable strategy to combat oxidative stress in the retina.
authors: From the Departments of Ophthalmology and Visual Sciences.
authors: Casey D
authors: CD
authors: Charvet
authors: Aicha
authors: A
authors: Saadane
authors: Meiyao
authors: M
authors: Wang
authors: Robert G
authors: RG
authors: Salomon
authors: Henri
authors: H
authors: Brunengraber
authors: Illarion V
authors: IV
authors: Turko
authors: Irina A
authors: IA
authors: Pikuleva
mesh_terms: D000368:Aged; D000818:Animals; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D005231:Fatty Acids, Unsaturated / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008027:Light; D008268:Macular Degeneration / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D011733:Pyridoxamine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D014803:Vitamin B Complex / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; C526910:iso(4)levuglandin E2; D014803:Vitamin B Complex; D011733:Pyridoxamine
keywords: Age-related Macular Degeneration; Isolevuglandin; Lipid Peroxidation; Mass Spectrometry (MS); Mitochondria; Oxidative Stress; Pyridoxamine; Retinal Degeneration; Vitamin B6
references: J Cell Physiol. 1992 Jul;152(1):102-10
references: 1618912
references: Free Radic Biol Med. 2012 Jul 1;53(1):64-71
references: 22579919
references: J Biol Chem. 2003 Oct 24;278(43):42027-35
references: 12923198
references: Vis Neurosci. 2002 Jul-Aug;19(4):395-407
references: 12511073
references: Lancet. 1965 Mar 20;1(7386):624-6
references: 14255214
references: Science. 1988 Jul 8;241(4862):215-8
references: 2455346
references: Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2696-701
references: 8610103
references: J Alzheimers Dis. 2011;27(1):49-59
references: 21709376
references: Chem Res Toxicol. 1997 Jul;10(7):750-9
references: 9250408
references: J Lipid Res. 2010 May;51(5):999-1009
references: 19965577
references: Anat Rec. 1972 Jul;173(3):309-23
references: 5039085
references: Chem Phys Lipids. 2004 Mar;128(1-2):85-99
references: 15037155
references: Adv Prostaglandin Thromboxane Leukot Res. 1985;15:323-6
references: 2936114
references: J Neurochem. 1989 Feb;52(2):381-9
references: 2911023
references: Neurobiol Aging. 2006 Jul;27(7):983-93
references: 15979212
references: Nature. 1993 Jul 29;364(6436):396
references: 8332209
references: Mutat Res. 1984 Oct;129(1):39-46
references: 6387469
references: Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2343-51
references: 10892882
references: Photochem Photobiol. 2009 Sep-Oct;85(5):1116-25
references: 19500292
references: Arch Ophthalmol. 2009 Dec;127(12):1678-9
references: 20008727
references: Invest Ophthalmol Vis Sci. 2008 Sep;49(9):3961-9
references: 18469195
references: J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):317-26
references: 16763894
references: Prog Retin Eye Res. 2001 Mar;20(2):175-208
references: 11173251
references: J Am Chem Soc. 2009 Sep 16;131(36):13037-44
references: 19705847
references: J Biol Chem. 2008 Sep 5;283(36):25091-102
references: 18606814
references: Am J Clin Nutr. 1993 May;57(5 Suppl):779S-785S; discussion 785S-786S
references: 8475896
references: Biochemistry. 2008 Jan 15;47(2):817-25
references: 18085799
references: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14682-7
references: 12391305
references: Circ Res. 2005 Dec 9;97(12):1262-9
references: 16284182
references: J Neurochem. 2005 Aug;94(4):1140-5
references: 15992375
references: J Neurosci. 2001 May 1;21(9):3017-23
references: 11312286
references: Exp Eye Res. 2004 Aug;79(2):239-47
references: 15325571
references: Chem Biodivers. 2011 Jul;8(7):1318-32
references: 21766453
references: Clin Chem. 2006 Apr;52(4):601-23
references: 16484333
references: J Lipid Res. 2012 Dec;53(12):2525-45
references: 22904344
references: J Org Chem. 2000 Aug 25;65(17):5315-26
references: 10993361
references: JAMA. 2002 Jun 26;287(24):3230-7
references: 12076219
references: Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3859-68
references: 16186375
references: Environ Health Perspect. 1990 Aug;88:99-106
references: 2272339
references: Free Radic Biol Med. 2010 Jan 1;48(1):16-25
references: 19686838
references: Invest Ophthalmol Vis Sci. 1993 Oct;34(11):3187-93
references: 8407228
references: J Biol Chem. 2008 Sep 26;283(39):26684-93
references: 18658157
references: J Lipid Res. 2013 May;54(5):1421-9
references: 23479405
references: Circulation. 2004 Aug 3;110(5):637-41
references: 15289389
references: J Biol Chem. 2011 Jun 10;286(23):20413-22
references: 21498512
references: FASEB J. 2003 Dec;17(15):2209-20
references: 14656983
references: J Neurochem. 1997 May;68(5):2092-7
references: 9109537
references: Arch Ophthalmol. 2001 Oct;119(10):1417-36
references: 11594942
references: Diabetes. 2002 Sep;51(9):2826-32
references: 12196477
references: J Neurosci. 2006 May 10;26(19):5256-64
references: 16687518
references: J Biol Chem. 1999 May 7;274(19):13139-46
references: 10224068
references: Ophthalmic Epidemiol. 2004 Apr;11(2):67-115
references: 15255026
references: Trends Cardiovasc Med. 2000 Feb;10(2):53-9
references: 11150730
references: Free Radic Biol Med. 1996;20(2):215-23
references: 8746442
references: J Biol Chem. 2001 Jun 22;276(25):23000-8
references: 11278285
references: Am J Pathol. 2003 Feb;162(2):413-25
references: 12547700
references: Mol Vis. 2009 Jun 01;15:1079-91
references: 19503745
references: Prog Lipid Res. 1983;22(2):79-131
references: 6348799
references: J Phys Chem A. 2012 Mar 22;116(11):2961-71
references: 22369344
references: J Am Soc Nephrol. 2012 Jan;23(1):131-6
references: 22034637
references: Curr Opin Ophthalmol. 2010 May;21(3):184-9
references: 20216418
references: Nat Med. 2008 Feb;14(2):194-8
references: 18223656
references: J Biol Chem. 2000 Jul 14;275(28):21177-84
references: 10801874
references: Behav Genet. 2002 Nov;32(6):435-43
references: 12467341
references: Neuroscience. 2004;129(3):779-90
references: 15541899
references: Methods Mol Biol. 2009;554:165-81
references: 19513674
references: Surv Ophthalmol. 2000 Sep-Oct;45(2):115-34
references: 11033038
references: Oncogene. 2013 Oct 17;32(42):4995-5004
references: 23334322
references: Free Radic Biol Med. 1988;4(2):99-106
references: 3278952
references: Biochemistry. 2006 Dec 26;45(51):15756-67
references: 17176098
references: Anal Biochem. 2008 Jun 1;377(1):55-61
references: 18384735
references: J Neurosci. 2001 Jan 1;21(1):53-8
references: 11150319
references: Kidney Int. 2002 Mar;61(3):939-50
references: 11849448
references: Neurobiol Aging. 1998 Jan-Feb;19(1):33-6
references: 9562500
references: Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13480-4
references: 16938854
references: Free Radic Res. 2005 Aug;39(8):875-82
references: 16036368
references: J Biol Chem. 1999 Jul 16;274(29):20271-80
references: 10400646
references: Free Radic Res. 2006 Aug;40(8):799-807
references: 17015258
references: Brain Res. 2008 Jan 16;1189:58-69
references: 18048005
references: Arch Biochem Biophys. 2003 Nov 1;419(1):41-9
references: 14568007
references: Free Radic Biol Med. 1991;11(1):81-128
references: 1937131
references: Curr Eye Res. 1987 Jun;6(6):825-34
references: 3608569
references: Am J Nephrol. 2007;27(6):605-14
references: 17823506
references: Free Radic Biol Med. 2009 Dec 1;47(11):1539-52
references: 19751823
references: Free Radic Biol Med. 2010 Aug 15;49(4):567-79
references: 20472054
references: Anal Chim Acta. 2012 Jan 27;712:108-14
references: 22177072
references: Invest Ophthalmol. 1966 Oct;5(5):450-73
references: 5929286
references: J Biol Chem. 2002 Mar 1;277(9):7183-90
references: 11756445
references: J Clin Invest. 2012 Aug;122(8):3012-23
references: 22820291
references: Chem Res Toxicol. 1997 Dec;10(12):1387-96
references: 9437530
references: J Clin Invest. 1990 Dec;86(6):1991-8
references: 2123889
references: J Lipid Res. 2003 May;44(5):917-26
references: 12588949
references: Mol Vis. 2004 Aug 26;10:598-607
references: 15354085
references: Prog Retin Eye Res. 2005 Mar;24(2):275-306
references: 15610977
references: Nat Chem Biol. 2011 Dec 25;8(2):170-8
references: 22198730
references: Chem Res Toxicol. 1995 Jan-Feb;8(1):61-7
references: 7703368