Purpose: Abnormalities in electroretinograms (ERG), such as reduced amplitudes and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are one of the earliest features of diabetic retinopathy prior to obvious vascular changes in diabetic retinas. We have previously shown that serum levels of advanced glycation end products (AGEs) are correlated with a delayed latency of OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG abnormalities remains unclear. We examined here whether high-affinity DNA aptamer directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental type 1 diabetic retinopathy. Methods: Streptozotocin-induced diabetic rats or control rats received continuous intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were measured, and an ERG was performed. Results: Although AGE-aptamer did not affect body weight, fasting and random blood glucose, HbA1c, blood pressure, or lipid parameters, it completely prevented the increase in serum AGE levels as well as the reduction of a- and b-wave and OP amplitudes in diabetic rats. Conclusion: The present study demonstrated for the first time that AGE-aptamer prevents abnormalities in ERG in experimental diabetic retinopathy probably by blocking the harmful effects of AGEs.

Keywords:
Advanced glycation end products, Electroretinogram, Aptamer, Diabetic retinopathy
1.
Monnier VM: Nonenzymatic glycosylation, the Maillard reaction and the aging process. J Gerontol 1990;45:B105-B111.
2.
Yamagishi S, Imaizumi T: Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 2005;11:2279-2299.
3.
Vlassara H, Striker GE: Advanced glycation end products in diabetes and diabetic complications. Endocrinol Metab Clin North Am 2013;42:697-719.
4.
Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y, Yoshida Y, Matsuura T, Narama I, Motomiya Y, Takeuchi M, Inoue H, Yoshimura A, Bucala R, Imaizumi T: Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem 2006;281:20213-20220.
5.
Yamagishi S, Matsui T, Nakamura K, Takeuchi M, Imaizumi T: Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis. Microvasc Res 2006;72:86-90.
6.
Yamagishi S, Matsui T: Advanced glycation end products (AGEs), oxidative stress and diabetic retinopathy. Curr Pharm Biotechnol 2011;12:362-368.
7.
Chen M, Curtis TM, Stitt AW: Advanced glycation end products and diabetic retinopathy. Curr Med Chem 2013;20:3234-3240.
8.
Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM: Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab 2014;25:15-22.
9.
Fletcher EL, Phipps JA, Ward MM, Puthussery T, Wilkinson-Berka JL: Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr Pharm Des 2007;13:2699-2712.
10.
Segawa Y, Shirao Y, Yamagishi S, Higashide T, Kobayashi M, Katsuno K, Iyobe A, Harada H, Sato F, Miyata H, Asai H, Nishimura A, Takahira M, Souno T, Segawa Y, Maeda K, Shima K, Mizuno A, Yamamoto H, Kawasaki K: Upregulation of retinal vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy: a possible participation of advanced glycation end products in the development of the early phase of diabetic retinopathy. Ophthalmic Res 1998;30:333-339.
11.
Pardue MT, Barnes CS, Kim MK, Aung MH, Amarnath R, Olson DE, Thulé PM: Rodent hyperglycemia-induced inner retinal deficits are mirrored in human diabetes. Transl Vis Sci Technol 2014;3:6.
12.
Simó R, Hernández C; European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR): Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab 2014;25:23-33.
13.
Ahn JS, Choi S, Jang SH, Chang HJ, Kim JH, Nahm KB, Oh SW, Choi EY: Development of a point-of-care assay system for high-sensitivity C-reactive protein in whole blood. Clin Chim Acta 2003;332:51-59.
14.
Tahara N, Yamagishi S, Takeuchi M, Honda A, Tahara A, Nitta Y, Kodama N, Mizoguchi M, Kaida H, Ishibashi M, Hayabuchi N, Matsui T, Imaizumi T: Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F]fluorodeoxyglucose positron emission tomography. Diabetes Care 2012;35:2618-2625.
15.
Higashimoto Y, Matsui T, Nishino Y, Taira J, Inoue H, Takeuchi M, Yamagishi S: Blockade by phosphorothioate aptamers of advanced glycation end products-induced damage in cultured pericytes and endothelial cells. Microvasc Res 2013;90:64-70.
16.
Kaida Y, Fukami K, Matsui T, Higashimoto Y, Nishino Y, Obara N, Nakayama Y, Ando R, Toyonaga M, Ueda S, Takeuchi M, Inoue H, Okuda S, Yamagishi S: DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. Diabetes 2013;62:3241-3250.
17.
Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, Fukami K, Yamagishi S: Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol 2013;182:132-141.
18.
Yoshida Y, Yamagishi S, Matsui T, Jinnouchi Y, Fukami K, Imaizumi T, Yamakawa R: Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy. Diabetes Metab Res Rev 2009;25:678-686.
19.
Carrasco E, Hernandez C, Miralles A, Huguet P, Farres J, Simó R: Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 2007;30:2902-2908.
20.
Ng JS, Bearse MA Jr, Schneck ME, Barez S, Adams AJ: Local diabetic retinopathy prediction by multifocal ERG delays over 3 years. Invest Ophthalmol Vis Sci 2008;49:1622-1628.
21.
Harrison WW, Bearse MA, Ng J, Jewell NP, Barez S, Burger D, Schneck ME, Adams AJ: Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. Invest Ophthalmol Vis Sci 2011;52:772-777.
22.
Barile GR, Pachydaki SI, Tari SR, Lee SE, Donmoyer CM, Ma W, Rong LL, Buciarelli LG, Wendt T, Hörig H, Hudson BI, Qu W, Weinberg AD, Yan SF, Schmidt AM: The RAGE axis in early diabetic retinopathy. Invest Ophthalmol Vis Sci 2005;46:2916-2924.
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2015
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