Abstract
Purpose
To evaluate the association between ocular blood flow and biomarkers of systemic oxidative stress, as well as the potential of these biomarkers to assess normal-tension glaucoma (NTG).
Methods
This study included 73 eyes of 73 patients with NTG. We assessed ocular blood flow by measuring mean blur rate (MBR) in the optic nerve head using laser speckle flowgraphy, both overall and separately in the vessel and tissue areas. We also measured urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG) and skin autofluorescence (SAF), and lastly, determined correlations between these measurements and with other clinical parameters.
Results
SAF was correlated with age, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), mean deviation (MD), and overall MBR (P = 0.003, P = 0.013, P = 0.015 and P = 0.006, respectively). SAF and 8-OHdG were both correlated with tissue-area MBR (P = 0.006 and P = 0.010, respectively). Visual acuity, cpRNFLT, mean deviation and tissue-area MBR had a significant tendency to change with NTG severity (P = 0.014, P < 0.001, P < 0.001 and P = 0.006, respectively). Multiple regression analysis revealed that cpRNFLT and 8-OHdG were independent contributing factors to MD (P < 0.001 and P = 0.040, respectively), and that cpRNFLT and 8-OHdG were independent contributing factors to tissue-area MBR (P = 0.005 and P = 0.028, respectively).
Conclusions
We found a close relationship between cpRNFLT, MD, tissue MBR, SAF and 8-OHdG, suggesting that systemic oxidative stress is associated with decreased ocular blood flow and may be involved in the pathogenesis of NTG.
Similar content being viewed by others
References
Izzotti A, Bagnis A, Saccà SC (2006) The role of oxidative stress in glaucoma. Mutat Res 612(2):105–114
Ferreira SM, Lerner SF, Brunzini R, Reides CG, Evelson PA, Llesuy SF (2010) Time course changes of oxidative stress markers in a rat experimental glaucoma model. Invest Ophthalmol Vis Sci 51(9):4635–4640
Sullivan RK, Woldemussie E, Macnab L, Ruiz G, Pow DV (2006) Evoked expression of the glutamate transporter GLT-1c in retinal ganglion cells in human glaucoma and in a rat model. Invest Ophthalmol Vis Sci 47(9):3853–3859
Neufeld AH, Sawada A, Becker B (1999) Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A 96(17):9944–9948
Iwase A, Suzuki Y, Araie M, Yamamoto T, Abe H, Shirato S, Kuwayama Y, Mishima HK, Shimizu H, Tomita G, Inoue Y, Kitazawa Y, Tajimi Study Group JpGS (2004) The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 111(9):1641–1648
Bagnis A, Izzotti A, Saccà SC (2012) Helicobacter pylori, oxidative stress and glaucoma. Dig Liver Dis
Engin KN, Yemişci B, Yiğit U, Ağaçhan A, Coşkun C (2010) Variability of serum oxidative stress biomarkers relative to biochemical data and clinical parameters of glaucoma patients. Mol Vis 16:1260–1271
Tamaki Y, Araie M, Kawamoto E, Eguchi S, Fujii H (1994) Noncontact, two-dimensional measurement of retinal microcirculation using laser speckle phenomenon. Invest Ophthalmol Vis Sci 35(11):3825–3834
Tamaki Y, Araie M, Kawamoto E, Eguchi S, Fujii H (1995) Non-contact, two-dimensional measurement of tissue circulation in choroid and optic nerve head using laser speckle phenomenon. Exp Eye Res 60(4):373–383
Sugiyama T, Utsumi T, Azuma I, Fujii H (1996) Measurement of optic nerve head circulation: comparison of laser speckle and hydrogen clearance methods. Jpn J Ophthalmol 40(3):339–343
Araie M (2000) In vivo measurement of ocular circulation with the laser speckle method-development of apparatus and application in ophthalmological research. Jpn J Ophthalmol 44(3):322–323
Yaoeda K, Shirakashi M, Funaki S, Funaki H, Nakatsue T, Fukushima A, Abe H (2000) Measurement of microcirculation in optic nerve head by laser speckle flowgraphy in normal volunteers. Am J Ophthalmol 130(5):606–610
Konishi N, Tokimoto Y, Kohra K, Fujii H (2002) New laser speckle flowgraphy system using CCD camera. Opt Rev 9(4):163–169
Satilmis M, Orgül S, Doubler B, Flammer J (2003) Rate of progression of glaucoma correlates with retrobulbar circulation and intraocular pressure. Am J Ophthalmol 135(5):664–669
Aizawa N, Kunikata H, Shiga Y, Yokoyama Y, Omodaka K, Nakazawa T (2014) Correlation between structure/function and optic disc microcirculation in myopic glaucoma, measured with laser speckle flowgraphy. BMC Ophthalmol 14:113
Aizawa N, Kunikata H, Yokoyama Y, Nakazawa T (2013) Correlation between optic disc microcirculation in glaucoma measured with laser speckle flowgraphy and fluorescein angiography, and the correlation with mean deviation. Clin Exp Ophthalmol 42(3):293–294. doi:10.1111/ceo.12130
Chiba N, Omodaka K, Yokoyama Y, Aizawa N, Tsuda S, Yasuda M, Otomo T, Yokokura S, Fuse N, Nakazawa T (2011) Association between optic nerve blood flow and objective examinations in glaucoma patients with generalized enlargement disc type. Clin Ophthalmol (Auckland, NZ) 5:1549–1556
Sugiyama T, Kojima S, Ishida O, Ikeda T (2009) Changes in optic nerve head blood flow induced by the combined therapy of latanoprost and beta blockers. Acta Ophthalmol 87(7):797–800
Sugiyama T, Mashima Y, Yoshioka Y, Oku H, Ikeda T (2009) Effect of unoprostone on topographic and blood flow changes in the ischemic optic nerve head of rabbits. Arch Ophthalmol 127(4):454–459
Yokoyama Y, Aizawa N, Chiba N, Omodaka K, Nakamura M, Otomo T, Yokokura S, Fuse N, Nakazawa T (2011) Significant correlations between optic nerve head microcirculation and visual field defects and nerve fiber layer loss in glaucoma patients with myopic glaucomatous disk. Clin Ophthalmol (Auckland, NZ) 5:1721–1727
Kobayashi W, Kunikata H, Omodaka K, Togashi K, Ryu M, Akiba M, Takeuchi G, Yuasa T, Nakazawa T (2014) Correlation of optic nerve microcirculation with papillomacular bundle structure in treatment naive normal tension glaucoma. J Ophthalmol 2014:468908
Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, Renard JP, Stefansson E (2002) The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 21(4):359–393
Inoue S, Takemoto M, Chishaki A, Ide T, Nishizaka M, Miyazono M, Sawatari H, Sunagawa K (2012) Leg heating using far infra-red radiation in patients with chronic heart failure acutely improves the hemodynamics, vascular endothelial function, and oxidative stress. Intern Med 51(17):2263–2270
Nozawa Y, Ishizaki T, Kuroda M, Noguchi T (2008) Effect of dried-bonito broth intake on peripheral blood flow, mood, and oxidative stress marker in humans. Physiol Behav 93(1–2):267–273
Yao QH, Mei SR, Weng QF, Zhang PD, Yang Q, Wu CY, Xu GW (2004) Determination of urinary oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine and the association with cigarette smoking. Talanta 63(3):617–623
Yuki K, Tsubota K (2013) Increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG)/creatinine level is associated with the progression of normal-tension glaucoma. Curr Eye Res 38(9):983–988
Nagaraj RH, Linetsky M, Stitt AW (2012) The pathogenic role of Maillard reaction in the aging eye. Amino Acids 42(4):1205–1220
Isono H, Kishi S, Kimura Y, Hagiwara N, Konishi N, Fujii H (2003) Observation of choroidal circulation using index of erythrocytic velocity. Arch Ophthalmol 121(2):225–231
Meerwaldt R, Graaff R, Oomen PH, Links TP, Jager JJ, Alderson NL, Thorpe SR, Baynes JW, Gans RO, Smit AJ (2004) Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 47(7):1324–1330
Yasuda M, Shimura M, Kunikata H, Kanazawa H, Yasuda K, Tanaka Y, Konno H, Takahashi M, Kokubun T, Maruyama K, Sato N, Kakizaki M, Sato M, Tsuji I, Miyata T, Nakazawa T (2015) Relationship of skin autofluorescence to severity of retinopathy in type 2 diabetes. Curr Eye Res 40(3):338–345
Rall LC, Roubenoff R, Meydani SN, Han SN, Meydani M (2000) Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of oxidative stress in rheumatoid arthritis and aging: effect of progressive resistance training. J Nutr Biochem 11(11–12):581–584
Tezel G, Luo C, Yang X (2007) Accelerated aging in glaucoma: immunohistochemical assessment of advanced glycation end products in the human retina and optic nerve head. Invest Ophthalmol Vis Sci 48(3):1201–1211
Harada T, Harada C, Nakamura K, Quah HM, Okumura A, Namekata K, Saeki T, Aihara M, Yoshida H, Mitani A, Tanaka K (2007) The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. J Clin Invest 117(7):1763–1770
Himori N, Yamamoto K, Maruyama K, Ryu M, Taguchi K, Yamamoto M, Nakazawa T (2013) Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death. J Neurochem 127(5):669–680
Sacca SC, Pascotto A, Camicione P, Capris P, Izzotti A (2005) Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol 123(4):458–463
Izzotti A, Sacca SC, Cartiglia C, De Flora S (2003) Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients. Am J Med 114(8):638–646
Sorkhabi R, Ghorbanihaghjo A, Javadzadeh A, Rashtchizadeh N, Moharrery M (2011) Oxidative DNA damage and total antioxidant status in glaucoma patients. Mol Vis 17:41–46
Tanito M, Kaidzu S, Takai Y, Ohira A (2012) Status of systemic oxidative stresses in patients with primary open-angle glaucoma and pseudoexfoliation syndrome. PLoS One 7(11), e49680
Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y (2008) Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol 28(9):1634–1639
Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF (2001) Oxidative stress and vascular damage in hypertension. Curr Opin Nephrol Hypertens 10(2):247–255
Minuz P, Fava C, Cominacini L (2006) Oxidative stress, antioxidants, and vascular damage. Br J Clin Pharmacol 61(6):774–777
Liu R, Liu H, Ha Y, Tilton RG, Zhang W (2014) Oxidative stress induces endothelial cell senescence via downregulation of Sirt6. Biomed Res Int 2014:902842
Pache M, Kaiser HJ, Akhalbedashvili N, Lienert C, Dubler B, Kappos L, Flammer J (2003) Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis. Eur Neurol 49(3):164–168
Andrews RM, Griffiths PG, Johnson MA, Turnbull DM (1999) Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina. Br J Ophthalmol 83(2):231–235
Jia Y, Morrison JC, Tokayer J, Tan O, Lombardi L, Baumann B, Lu CD, Choi W, Fujimoto JG, Huang D (2012) Quantitative OCT angiography of optic nerve head blood flow. Biomed Opt Express 3(12):3127–3137
Aizawa N, Nitta F, Kunikata H, Sugiyama T, Ikeda T, Araie M, Nakazawa T (2014) Laser speckle and hydrogen gas clearance measurements of optic nerve circulation in albino and pigmented rabbits with or without optic disc atrophy. Invest Ophthalmol Vis Sci 55(12):7991–7996
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382(6593):685–691
Ma L, Nicholson LF (2004) Expression of the receptor for advanced glycation end products in Huntington's disease caudate nucleus. Brain Res 1018(1):10–17
Meerwaldt R, Zeebregts CJ, Navis G, Hillebrands JL, Lefrandt JD, Smit AJ (2009) Accumulation of advanced glycation end products and chronic complications in ESRD treated by dialysis. Am J Kidney Dis 53(1):138–150
Hirano T, Iesato Y, Toriyama Y, Imai A, Chiba D, Murata T (2014) Correlation between diabetic retinopathy severity and elevated skin autofluorescence as a marker of advanced glycation end-product accumulation in type 2 diabetic patients. J Diabetes Complicat 28(5):729–734
Begum VU, Addepalli UK, Yadav RK, Shankar K, Senthil S, Garudadri CS, Rao HL (2014) Ganglion cell-inner plexiform layer thickness of high definition optical coherence tomography in perimetric and preperimetric glaucoma. Invest Ophthalmol Vis Sci 55(8):4768–4775
Moran C, Munch G, Forbes JM, Beare R, Blizzard L, Venn AJ, Phan TG, Chen J, Srikanth V (2015) Type 2 diabetes, skin autofluorescence, and brain atrophy. Diabetes 64(1):279–283
Metta S, Basalingappa DR, Uppala S, Mitta G (2015) Erythrocyte antioxidant defenses against cigarette smoking in ischemic heart disease. J Clin Diagn Res 9(6):Bc08-11
Acknowledgments
We thank Mr. Tim Hilts for reviewing and editing the language of the manuscript, and Ms. Akane Enta and Mr. Nobuo Akiyama for technical assistance. This paper was supported in part by a JSPS KAKEN Grant-in-Aid for young scientists (N.H, 26861434), a JST grant from JSPS KAKENHI Grants-in-Aid for Scientific Research (B) (T.N. 26293372) and for Exploratory Research (T.N. 26670751), and by the JST Center for Revitalization Promotion. There is no commercial financial support to report. There were no competing financial interests in this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for this research.
Conflict of interest
All authors certify that they have no affiliations with or involvement in any organization or entry with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Himori, N., Kunikata, H., Shiga, Y. et al. The association between systemic oxidative stress and ocular blood flow in patients with normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 254, 333–341 (2016). https://doi.org/10.1007/s00417-015-3203-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00417-015-3203-z