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Protective effects of resveratrol and its analogs on age-related macular degeneration in vitro

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Abstract

Damage of retinal pigment epithelial (RPE) cells by A2E may be critical for age-related macular degeneration (AMD) management. Accumulation and photooxidation of A2E are known to be one of the critical causes in AMD. Here, we evaluated the protective effect of resveratrol (RES), piceatannol (PIC) and RES glycones on blue-light-induced RPE cell death caused by A2E photooxidation. A2E treatment followed by blue light exposure caused significant damages on human RPE cells (ARPE-19). But the damages were attenuated by post- and pre-treatment of RES and PIC in our in vitro models. The results of cell free system and FAB-MS analysis clearly showed that the reduction of A2E by blue light exposure was significantly rescued, and that oxidized forms of A2E were significantly reduced by RES or PIC treatment. Besides, RES or PIC inhibited the intracellular accumulation of A2E. Not only RES and PIC but RES glycones showed protection of ARPE-19 cells against A2E and blue-light-induced photo-damage. These findings demonstrate that RES and its analogs may have protective effects against A2E and blue-light-induced ARPE-19 cell death through regulation of A2E accumulation as well as photooxidation of A2E. Thus RES and its analogs may be beneficial for AMD treatment.

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References

  • Barreiro S, Marcheselli V, Bazan N (2005) Human retinal pigment epithelial cells protected by NPD–1 After A2E–epoxide induction. Invest Ophthalmol Vis Sci 46:250

    Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ, Nakanishi K (2002) Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Edit 41:814–817

    Article  CAS  Google Scholar 

  • Bhosale P, Serban B, Bernstein PS (2009) Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium. Arch Biochem Biophys 483:175–181

    Article  CAS  PubMed  Google Scholar 

  • Chakravarthy U, Evans J, Rosenfeld PJ (2010) Age related macular degeneration. Bmj 340:256–530

    Google Scholar 

  • Chen Y, Yang P, Li F, Kijlstra A (2011) The effects of Th17 cytokines on the inflammatory mediator production and barrier function of ARPE-19 cells. PLoS One 6:e18139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Das S, Ng KY (2010) Resveratrol-loaded calcium-pectinate beads: effects of formulation parameters on drug release and bead characteristics. J Pharm Sci 99:840–860

    Article  CAS  PubMed  Google Scholar 

  • Evans JB, Syed BA (2013) New hope for dry AMD? Nat Rev Drug Discov 12:501–502

    Article  CAS  PubMed  Google Scholar 

  • Fabre KM, Saito K, DeGraff W, Sowers AL, Thetford A, Cook JA, Krishna MC, Mitchell JB (2011) The effects of resveratrol and selected metabolites on the radiation and antioxidant response. Cancer Biol Ther 12:915–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang Y, Su T, Qiu X, Mao P, Xu Y, Hu Z, Zhang Y, Zheng X, Xie P, Liu Q (2016) Protective effect of alpha-mangostin against oxidative stress induced-retinal cell death. Sci Rep 6:21018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farjo KM, Farjo RA, Halsey S, Moiseyev G, J-x Ma (2012) Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase-and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol 32:5103–5115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heebøll S, Thomsen KL, Pedersen SB, Vilstrup H, George J, Grønbæk H (2014) Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease. World J Hepatol 6:188

    Article  PubMed  PubMed Central  Google Scholar 

  • Höhn A, Jung T, Grimm S, Grune T (2010) Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radic Biol Med 48:1100–1108

    Article  PubMed  Google Scholar 

  • Holz FG, Bellman C, Staudt S, Schütt F, Völcker HE (2001) Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 42:1051–1056

    CAS  PubMed  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang L-L (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  CAS  PubMed  Google Scholar 

  • Hung C-F, Chan C-M, Su C-C (2015) Protective effects of resveratrol against UVA-induced damage in ARPE19 cells. FASEB J 29(621):9

    Google Scholar 

  • Hunter A, Spechler P, Cwanger A, Song Y, Zhang Z, G-s Ying, Hunter AK, Dunaief J (2012) DNA methylation is associated with altered gene expression in AMD. Invest Ophthalmol Vis Sci 52:5980

    Google Scholar 

  • Jang YP, Zhou J, Nakanishi K, Sparrow JR (2005) Anthocyanins protect against A2E photooxidation and membrane permeabilization in retinal pigment epithelial cells. Photochem Photobiol 81:529–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin HL, Lee S-C, Kwon YS, Choung S-Y, Jeong KW (2016) A novel fluorescence-based assay for measuring A2E removal from human retinal pigment epithelial cells to screen for age-related macular degeneration inhibitors. J Pharm Biomed Anal 117:560–567

    Article  CAS  PubMed  Google Scholar 

  • Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K (2012) Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells—implications for age-related macular degeneration (AMD). Immunol Lett 147:29–33

    Article  CAS  PubMed  Google Scholar 

  • Kelsey NA, Wilkins HM, Linseman DA (2010) Nutraceutical antioxidants as novel neuroprotective agents. Molecules 15:7792–7814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King RE, Kent KD, Bomser JA (2005) Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem Biol Interact 151:143–149

    Article  CAS  PubMed  Google Scholar 

  • Kuse Y, Ogawa K, Tsuruma K, Shimazawa M, Hara H (2014) Damage of photoreceptor-derived cells in culture induced by light emitting diode-derived blue light. Sci Rep 4

  • Lançon A, Michaille JJ, Latruffe N (2013) Effects of dietary phytophenols on the expression of microRNAs involved in mammalian cell homeostasis. J Sci Food Agric 93:3155–3164

    Article  PubMed  Google Scholar 

  • Lanzilli G, Cottarelli A, Nicotera G, Guida S, Ravagnan G, Fuggetta MP (2012) Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 35:240–248

    Article  CAS  PubMed  Google Scholar 

  • Lin HS, Yue BD, Ho PC (2009) Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre-clinical pharmacokinetic study. Biomed Chromatog 23:1308–1315

    Article  CAS  Google Scholar 

  • Lu X, Ji C, Xu H, Li X, Ding H, Ye M, Zhu Z, Ding D, Jiang X, Ding X (2009) Resveratrol-loaded polymeric micelles protect cells from Aβ-induced oxidative stress. Int J Pharm 375:89–96

    Article  CAS  PubMed  Google Scholar 

  • Maeda A, Maeda T, Golczak M, Palczewski K (2008) Retinopathy in mice induced by disrupted all-trans-retinal clearance. J Biol Chem 283:26684–26693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mimura T, Kaji Y, Noma H, Funatsu H, Okamoto S (2013) The role of SIRT1 in ocular aging. Exp Eye Res 116:17–26

    Article  CAS  PubMed  Google Scholar 

  • Oliveira BF, Nogueira-Machado JA, Chaves MM (2010) The role of oxidative stress in the aging process. Sci World J 10:1121–1128

    Article  CAS  Google Scholar 

  • Palamoor M, Jablonski MM (2013) Synthesis, characterization and in vitro studies of celecoxib-loaded poly (ortho ester) nanoparticles targeted for intraocular drug delivery. Colloids Surf B 112:474–482

    Article  CAS  Google Scholar 

  • Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow J (1998) Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Natl Acad Sci USA 95:14609–14613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pezzuto JM, Kondratyuk TP, Ogas T (2013) Resveratrol derivatives: a patent review (2009–2012). Expert Opin Ther Pat 23:1529–1546

    Article  CAS  PubMed  Google Scholar 

  • Polonini HC, Lima LL, Gonçalves KM, do Carmo AMR, da Silva AD, Raposo NRB (2013) Photoprotective activity of resveratrol analogues. Bioorg Med Chem 21:964–968

    Article  CAS  PubMed  Google Scholar 

  • Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH (2003) Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration. Proc Natl Acad Sci USA 100:4742–4747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickman CB, Farsiu S, Toth CA, Klingeborn M (2013) Dry age-related macular degeneration: mechanisms, therapeutic targets, and imagingdry AMD mechanisms, targets, and imaging. Invest Ophthalmol Vis Sci 54:ORSF68–ORSF80

    Article  Google Scholar 

  • Romano AD, Serviddio G, de Matthaeis A, Bellanti F, Vendemiale G (2009) Oxidative stress and aging. J Nephrol 23:S29–S36

    Google Scholar 

  • Rüweler M, Gülden M, Maser E, Murias M, Seibert H (2009) Cytotoxic, cytoprotective and antioxidant activities of resveratrol and analogues in C6 astroglioma cells in vitro. Chem Biol Interact 182:128–135

    Article  PubMed  Google Scholar 

  • Sadowska-Bartosz I, Bartosz G (2014) Effect of antioxidants supplementation on aging and longevity. Biomed Res Int

  • Sale S, Verschoyle RD, Boocock D, Jones D, Wilsher N, Ruparelia KC, Potter G, Farmer PB, Steward WP, Gescher AJ (2004) Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3, 4, 5, 4′-tetramethoxystilbene. Br J Cancer 90:736–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos AC, Veiga F, Ribeiro AJ (2011) New delivery systems to improve the bioavailability of resveratrol. Expert Opin Drug Deliv 8:973–990

    Article  CAS  PubMed  Google Scholar 

  • Shakibaei M, Harikumar KB, Aggarwal BB (2009) Resveratrol addiction: to die or not to die. Mol Nutr Food Res 53:115–128

    Article  CAS  PubMed  Google Scholar 

  • Sparrow JR, Boulton M (2005) RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 80:595–606

    Article  CAS  PubMed  Google Scholar 

  • Sparrow JR, Cai B (2001) Blue light–induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci 42:1356–1362

    CAS  PubMed  Google Scholar 

  • Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagaki Y, Nakanishi K (2002) Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 43:1222–1227

    PubMed  Google Scholar 

  • Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi K (2003a) A2E-epoxides damage DNA in retinal pigment epithelial cells vitamin E and other antioxidants inhibit A2E-epoxide formation. J Biol Chem 278:18207–18213

    Article  CAS  PubMed  Google Scholar 

  • Sparrow JR, Zhou J, Cai B (2003b) DNA is a target of the photodynamic effects elicited in A2E-laden RPE by blue-light illumination. Invest Ophthalmol Vis Sci 44:2245–2251

    Article  PubMed  Google Scholar 

  • Sparrrow JR, Hicks D, Hamel CP (2010) The retinal pigment epithelium in health and disease. Curr Mol Med 10:802–823

    Article  CAS  PubMed Central  Google Scholar 

  • Suri S, Liu X, Rayment S, Hughes D, Kroon P, Needs P, Taylor M, Tribolo S, Wilson V (2010) Quercetin and its major metabolites selectively modulate cyclic GMP-dependent relaxations and associated tolerance in pig isolated coronary artery. Br J Pharmacol 159:566–575

    Article  CAS  PubMed  Google Scholar 

  • Suter M, Remé C, Grimm C, Wenzel A, Jäättela M, Esser P, Kociok N, Leist M, Richter C (2000) Age-related macular degeneration the lipofuscin componentn-retinyl-n-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 275:39625–39630

    Article  CAS  PubMed  Google Scholar 

  • Švajger U, Jeras M (2012) Anti-inflammatory effects of resveratrol and its potential use in therapy of immune-mediated diseases. Int Rev Immunol 31:202–222

    Article  PubMed  Google Scholar 

  • Szekeres T, Fritzer-Szekeres M, Saiko P, Jäger W (2010) Resveratrol and resveratrol analogues—structure–activity relationship. Pharm Res 27:1042–1048

    Article  CAS  PubMed  Google Scholar 

  • Szekeres T, Saiko P, Fritzer-Szekeres M, Djavan B, Jäger W (2011) Chemopreventive effects of resveratrol and resveratrol derivatives. Ann N.Y. Acad Sci 1215:89–95

    Article  CAS  PubMed  Google Scholar 

  • Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD (2004) Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam eye study. Arch Ophthalmol 122:750–757

    Article  PubMed  Google Scholar 

  • Torres P, Poveda A, Jimenez-Barbero J, Parra JL, Comelles F, Ballesteros AO, Plou FJ (2011) Enzymatic synthesis of α-glucosides of resveratrol with surfactant activity. Adv Synth Catal 353:1077–1086

    Article  CAS  Google Scholar 

  • Tribolo S, Lodi F, Connor C, Suri S, Wilson VG, Taylor MA, Needs PW, Kroon PA, Hughes DA (2008) Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197:50–56

    Article  CAS  PubMed  Google Scholar 

  • van Lookeren Campagne M, LeCouter J, Yaspan BL, Ye W (2014) Mechanisms of age-related macular degeneration and therapeutic opportunities. J pathol 232:151–164

    Article  Google Scholar 

  • Vives-Bauza C, Anand M, Shirazi AK, Magrane J, Gao J, Vollmer-Snarr HR, Manfredi G, Finnemann SC (2008) The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. J Biol Chem 283:24770–24780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Dean DC, Kaplan HJ (2010) Age-related macular degeneration. Discov Med 9:13–15

    CAS  PubMed  Google Scholar 

  • Wang W, Sreekumar PG, Valluripalli V, Shi P, Wang J, Lin Y-A, Cui H, Kannan R, Hinton DR, MacKay JA (2014) Protein polymer nanoparticles engineered as chaperones protect against apoptosis in human retinal pigment epithelial cells. J Control Release 191:4–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei L, Liu B, Tuo J, Shen D, Chen P, Li Z, Liu X, Ni J, Dagur P, Sen H (2012) Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell Rep 2:1151–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenzel E, Soldo T, Erbersdobler H, Somoza V (2005) Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res 49:482–494

    Article  CAS  PubMed  Google Scholar 

  • Westlund BS, Cai B, Zhou J, Sparrow JR (2009) Involvement of c-Abl, p53 and the MAP kinase JNK in the cell death program initiated in A2E-laden ARPE-19 cells by exposure to blue light. Apoptosis 14:31–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wielgus A, Collier R, Martin E, Lih F, Tomer K, Chignell C, Roberts J (2010) Blue light induced A2E oxidation in rat eyes–experimental animal model of dry AMD. Photochem Photobiol Sci 9:1505–1512

    Article  CAS  PubMed  Google Scholar 

  • Wong YT, Gruber J, Jenner AM, Tay FEH, Ruan R (2011) Chronic resveratrol intake reverses pro-inflammatory cytokine profile and oxidative DNA damage in ageing hybrid mice. Age 33:229–246

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Fishkin NE, Pande A, Pande J, Sparrow JR (2009) Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease. J Biol Chem 284:20155–20166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Yanase E, Feng X, Siegel MM, Sparrow JR (2010) Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci USA 107:7275–7280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoon S-M, Lee B-L, Guo Y-R, Choung S-Y (2016) Preventive effect of Vaccinium uliginosum L. extract and its fractions on age-related macular degeneration and its action mechanisms. Arch Pharm Res 39:21–32

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, Sun T, Jiang Y, Wu L, Cai X, Sun X, Sun X (2014) Photooxidative damage in retinal pigment epithelial cells via GRP78 and the protective role of grape skin polyphenols. Food Chem Toxicol 74:216–224

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Jang YP, Kim SR, Sparrow JR (2006) Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci USA 103:16182–16187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Prof. Jae Kyung Sohng, Department of Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, Chungnam, Republic of Korea for his generous gift of three different types of RES glycones tested in this study.

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Correspondence to Se-Young Choung.

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Kang, JH., Choung, SY. Protective effects of resveratrol and its analogs on age-related macular degeneration in vitro. Arch. Pharm. Res. 39, 1703–1715 (2016). https://doi.org/10.1007/s12272-016-0839-0

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