Can allopurinol improve retinopathy in diabetic rats? Oxidative stress or uric acid; which one is the culprit?

Mohsen Goharinia, Athar Zareei, Mansour Rahimi, Hossein Mirkhani

Abstract


Allopurinol, an inhibitor of xanthine oxidase, reduces both plasma uric acid and oxidative stress and shows useful effects on some complications of diabetes. However, it is not defined which of the above mentioned properties are involved. Moreover, to the best of our knowledge no study has been done on the effects of allopurinol on diabetic retinopathy. In the present study, the effect of allopurinol on experimental diabetic retinopathy and its possible mechanism has been investigated. Thirty two rats were divided into four groups of eight rats each; (1) normal, (2) diabetic control, (3) diabetic + allopurinol (50 mg/kg.day), (4) diabetic + benzbromarone (10 mg/kg.day). Drugs were administered daily and orally from the day after diabetes induction for eight weeks. Thereafter retinal function and structure were evaluated by electroretinography and microscopic studies. Uric acid and oxidative stress biomarkers were measured biochemically. Diabetes significantly increased plasma uric acid and oxidative stress markers and reduced body weight and amplitude of electroretinogram (ERG) b-wave and oscillatory potentials. Treatment of diabetic rats with allopurinol caused a significant increase in the amplitude of ERG b-wave (87%) and decrease in blood sugar (20%), uric acid (49%), and 8-iso-prostaglandin F2α (56%), but had no effect on the number of retinal ganglionic cells and oscillatory potentials. Benzbromarone showed no significant effects on the considered parameters except the reduction of uric acid. Allopurinol improved the b-wave amplitude of diabetic rats. It seems that this beneficial effect is due to the reduction of oxidative stress rather than its effect on plasma uric acid.


Keywords


Diabetic retinopathy; Allopurinol; Benzbromarone; Electroretinography

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References


Liu X, Zhu B, Zou H, Hu D, Gu Q, Liu K, et al. Carbamylated erythropoietin mediates retinal neuroprotection in streptozotocin-induced early-stage diabetic rats. Graefes Arch Clin Exp Ophthalmol. 2015;253:1263-1272.

Cai X, McGinnis JF. Diabetic retinopathy: animal models, therapies, and perspectives. J Diabetes Res. 2016;2016:3789217.

Behl T, Kaur I, Kotwani A. Implication of oxidative stress in progression of diabetic retinopathy. Surv Ophthalmol. 2016;61:187-196.

Lorenzi K, Oates PJ. The polyol pathway and diabetic retinopathy. Diabetic Retinopathy: 2007;2007:610385. Kur J, Burian MA, Newman EA. Light adaptation does not prevent early retinal abnormalities in diabetic rats. Scientific reports. 2016;6.

Sun JK, Keenan HA, Cavallerano JD, Asztalos BF, Schaefer EJ, Sell DR, et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the joslin 50-year medalist study. Diabetes Care. 2011;34:968-74.

Afshari M, Larijani B, Rezaie A, Mojtahedi A, Zamani MJ, Astanehi-Asghari F, et al. Ineffectiveness of allopurinol in reduction of oxidative stress in diabetic patients; a randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother. 2004;58:546-50.

Kosugi T, Nakayama T, Heinig M, Zhang L, Yuzawa Y, Sanchez-Lozada LG, et al. Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice. Am J Physiol Renal Physiol. 2009;297:F481-F488.

Momeni A, Shahidi S, Seirafian S, Taheri S, Kheiri S. Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients. Iran J Kidney Dis. 2010;4:128-132.

Desco MC, Asensi M, Marquez R, Martinez-Valls J, Vento M, Pallardo FV, et al. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes. 2002;51(4):1118-1124.

George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114:2508-2516.

Inkster ME, Cotter MA, Cameron NE. Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats. Eur J Pharmacol. 2007;561:63-71.

Matsumoto S, Koshiishi I, Inoguchi T, Nawata H, Utsumi H. Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radic Res. 2003;37:767-772.

Kushiyama A, Tanaka K, Hara S, Kawazu S. Linking uric acid metabolism to diabetic complications. World J Diabetes. 2014;5:787-795.

Lee JJ, Yang IH, Kuo HK, Chung MS, Chen YJ, Chen CH, et al. Serum uric acid concentration is associated with worsening in severity of diabetic retinopathy among type 2 diabetic patients in Taiwan--a 3-year prospective study. Diabetes Res Clin Pract. 2014;106:366-372.

Mohora M, Virgolici B, Coman A, Muscurel C, Gaman L, Gruia V, et al. Diabetic foot patients with and without retinopathy and plasma oxidative stress. Rom J Intern Med. 2007;45:51-57.

Xia J, Wang Z, Zhang F. Association between related purine metabolites and diabetic retinopathy in type 2 diabetic patients. Int J Endocrinol. 2014;2014:651050.

Munteanu M, Sturza A, Schiller A, Timar R. Endothelial dysfunction in diabetes–clasic sources of vascular oxidative stress (nadph oxidases, enos uncoupling and xanthine oxidase). Rom J Diabetes Nut Metabol Dis. 2013;20:149-155.

Minaiyan M, Ghannadi A, Movahedian A, Hakim-Elahi I. Effect of Hordeum vulgare L. (Barley) on blood glucose levels of normal and STZ-induced diabetic rats. Res Pharm Sci. 2014;9:173-178.

Chen CC, Hsu YJ, Lee TM. Impact of elevated uric acid on ventricular remodeling in infarcted rats with experimental hyperuricemia. Am J Physiol Heart Circ Physiol. 2011;301:H1107-H1117.

Firuzi O, Shakibazad N, Amoozgar H, Borzoee M, Abtahi S, Ajami G, et al. Effects of omega-3 polyunsaturated fatty acids on heart function and oxidative stress biomarkers in pediatric patients with dilated cardiomyopathy. Int Cardiovasc Res J. 2013;7:8-14.

Dilsiz N, Sahaboglu A, Yildiz MZ, Reichenbach A. Protective effects of various antioxidants during ischemia-reperfusion in the rat retina. Graefes Arch Clin Exp Ophthalmol. 2006;244:627-633.

McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol. 2015;130:1-12.

Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest. 1998;102:783-791.

Lai AK, Lo AC. Animal models of diabetic retinopathy: summary and comparison. J Diabetes Res. 2013;2013:106594.

Frijhoff J, Winyard PG, Zarkovic N, Davies SS, Stocker R, Cheng D, et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal. 2015;23:1144-1170.

Sampson MJ, Gopaul N, Davies IR, Hughes DA, Carrier MJ. Plasma F2 isoprostanes: direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care. 2002;25:537-541.

Kusari J, Zhou S, Padillo E, Clarke KG, Gil DW. Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2007;48:5152-5159.

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(26):2699-2712.

Liu YJ, Lian ZY, Liu G, Zhou HY, Yang HJ. RNA sequencing reveals retinal transcriptome changes in STZinduced diabetic rats. Mol Med Rep. 2016;13:2101-2109.

Xin H, Zhou F, Liu T, Li GY, Liu J, Gao ZZ, et al. Icariin ameliorates streptozotocin-induced diabetic retinopathy in vitro and in vivo. Int J Mol Sci. 2012;13:866-878.

Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011;52:1156-1163.

Jung KI, Kim JH, Park HY, Park CK. Neuroprotective effects of cilostazol on retinal ganglion cell damage in diabetic rats. J Pharmacol Exp Ther. 2013;345:457-463.

Kohzaki K, Vingrys AJ, Bui BV. Early inner retinal dysfunction in streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2008;49:3595-3604.

Nasralah Z, Robinson W, Jackson GR, Barber AJ. Measuring visual function in diabetic retinopathy: progress in basic and clinical research. J Clin Exp Ophthalmol. 2013;2013.

Hou SZ, Liang CY, Liu HZ, Zhu DM, Wu YY, Liang J, et al. Dendrobium officinale prevents early complications in streptozotocin-induced diabetic rats. Evid Based Complement Alternat Med. 2016;2016:6385850.

Li Q, Zemel E, Miller B, Perlman I. Early retinal damage in experimental diabetes: electro-retinographical and morphological observations. Exp Eye Res. 2002;74:615-625.


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