Selim SEKKİN, Eda Duygu İPEK, Murat BOYACIOĞLU, Cavit KUM, Ümit KARADEMİR, Hande Sultan YALINKILINÇ, Mehmet Onur AK, Hulki BAŞALOĞLU

DNA protective and antioxidative effects of melatonin in streptozotocin-induced diabetic rats

Diabetes mellitus is a chronic disease characterized by elevated blood sugar levels. In diabetic patients, oxidative stress induced by the presence of excessive free radicals is closely associated with chronic in?ammation, leading to potential tissue damage. Melatonin (MEL) is a compound synthesized by the pineal gland and a scavenger of free radicals. The aim of this study was to research the effects of MEL on oxidative stress and its DNA protective effects in streptozotocin-induced diabetic rats. In total, 32 rats were equally divided into four experimental groups: control, melatonin, diabetic, and diabetic + melatonin. A single dose of streptozotocin (60 mg/kg) was given by intraperitoneal route to induce experimental diabetes. MEL (10 mg/kg daily) was administrated to rats by intraperitoneal route for 6 weeks. Oxidative stress parameters were evaluated in rat liver, kidney, brain, and pancreas tissues. Body weight, plasma glucose, and HbA1c levels were studied. DNA damage was analyzed by comet assay in lymphocytes, while % tail DNA and mean tail moment parameters were evaluated. The study results indicate that the intraperitoneal administration of 10 mg/kg MEL over 6 weeks may cause amelioration in oxidative stress parameters against diabetes, leading to beneficial effects based on % tail DNA and mean tail moment parameters in rat lymphocytes.

Anahtar Kelimeler:

Diabetes mellitus, comet assay, oxidative stress, melatonin, streptozotocin, DNA damage, MDA level, tail moment, % tail DNA, DNA repair

DNA protective and antioxidative effects of melatonin in streptozotocin-induced diabetic rats

Keywords:

Diabetes mellitus, comet assay, oxidative stress, melatonin, streptozotocin, DNA damage, MDA level, tail moment, % tail DNA, DNA repair,

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Aebi H (1984). Catalase in vitro assay methods. Methods Enzymol 105: 121–126.
Agil A, Reiter RJ, Jimenez-Aranda A, Iban-Arias R, Navarro-Alarcon M, Marchal JA, Adem A, Fernandez-Vazquez G (2013). Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats. J Pineal Res 54: 381– 388.
Aksoy N, Vural H, Sabuncu T, Aksoy S (2003). Effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin- induced diabetic rats. Cell Biochem Funct 21: 121–125.
Andersson AK, Sandler S (2001). Melatonin protects against streptozotocin, but not interleukin-1β-induced damage of rodent pancreatic beta-cells. J Pineal Res 30: 157–165.
Arif M, Islam MR, Waise TM, Hassan F, Mondal SI, Kabir Y (2010). DNA damage and plasma antioxidant indices in Bangladeshi type 2 diabetic patients. Diabetes Metab 36: 51–57.
Bibak B, Khalili M, Rajaei Z, Soukhtanloo M, Hadjzadeh MA, Hayatdavoudi P (2014). Effects of melatonin on biochemical factors and food and water consumption in diabetic rats. Adv Biomed Res 3: 173.
Brownlee M (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615–1625.
Cam M, Yavuz O, Guven A, Ercan F, Bukan N, Ustundag N (2003). Protective effects of chronic melatonin treatment against kidney injury in streptozotocin-induced diabetic rats. J Pineal Res 35: 212–220.
Carpentieri A, de Barboza GD, Areco V, López MP, de Talamoni NT (2012). New perspectives in melatonin uses. Pharmacol Res 65: 437–444.
Cemeli E, Baumgartner A, Anderson D (2009). Antioxidants and the Comet assay. Mutat Res 681: 51–67.
Collins A, Dušinská M, Franklin M, Somorovská M, Petrovská H, Duthie S, Fillion L, Panayiotidis M, Rašlová K, Vaughan N (1997). Comet assay in human biomonitoring studies: Reliability, validation, and applications. Environ Mol Mutagen 30: 139–146.
Collins AR (2014). Measuring oxidative damage to DNA and its repair with the comet assay. Biochim Biophys Acta 1840: 794– 800.
Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A (2006). Biomarkers of oxidative damage in human disease. Clin Chem 52: 601–623.
Dhawan A, Bajpayee M, Parmar D (2009). Comet assay: a reliable tool for the assessment of DNA damage in different models. Cell Biol Toxicol 25: 5–32.
Di Naso FC, Simoes Dias A, Porawski M, Marroni NA (2011). Exogenous superoxide dismutase: action on liver oxidative stress in animals with streptozotocin-induced diabetes. Exp Diabetes Res 2011: 754132.
Elbe H, Vardi N, Esrefoglu M, Ates B, Yologlu S, Taskapan C (2015). Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum Exp Toxicol 34: 100–113.
Eşrefoğlu M, Akıncı A, Elbe H, Taşlıdere E, Cetin A, Ateş B (2014). Melatonin is effective in reducing stress-induced organ damage in Wistar albino rats. Turk J Biol 38: 493–501.
Frode TS, Medeiros YS (2008). Animal models to test drugs with potential antidiabetic activity. J Ethnopharmacol 115: 173–183.
Garcia-Ramirez M, Francisco G, Garcia-Arumi E, Hernandez C, Martinez R, Andreu AL, Simo R (2008). Mitochondrial DNA oxidation and manganese superoxide dismutase activity in peripheral blood mononuclear cells from type 2 diabetic patients. Diabetes Metab 34: 117–124.
Giacco F, Brownlee M (2010). Oxidative stress and diabetic complications. Circ Res 107: 1058–1070.
Gleissner CA (2015). The vulnerable vessel. Vascular disease in diabetes mellitus. Hamostaseologie 35: 267–271.
Gorgun FM, Ozturk Z, Gumustas MK, Kokogu E (2002). Melatonin administration affects plasma total sialic acid and lipid peroxidation levels in streptozotocin induced diabetic rats. J Toxicol Environ Health A 65: 695–700.
Jangra A, Datusalia AK, Khandwe S, Sharma SS (2013). Amelioration of diabetes-induced neurobehavioral and neurochemical changes by melatonin and nicotinamide: implication of oxidative stress-PARP pathway. Pharmacol Biochem Behav 114–115: 43–51.
Korkmaz A, Ma S, Topal T, Rosales-Corral S, Tan DX, Reiter RJ (2012). Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state. Mol Cell Endocrinol 349: 128–137.
Kushwaha S, Vikram A, Trivedi PP, Jena GB (2011). Alkaline, Endo III and FPG modified comet assay as biomarkers for the detection of oxidative DNA damage in rats with experimentally induced diabetes. Mutat Res 726: 242–250.
Leon J, Acuna-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ (2004). Melatonin and mitochondrial function. Life Sci 75: 765–790.
Manda K, Ueno M, Anzai K (2007). AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res 42: 386–393.
Marrazzo G, Barbagallo I, Galvano F, Malaguarnera M, Gazzolo D, Frigiola A, D’Orazio N, Li Volti G (2014). Role of dietary and endogenous antioxidants in diabetes. Crit Rev Food Sci Nutr 54: 1599–1616.
Montilla PL, Vargas JF, Tunez IF, Munoz de Agueda MC, Valdelvira ME, Cabrera ES (1998). Oxidative stress in diabetic rats induced by streptozotocin: protective effects of melatonin. J Pineal Res 25: 94–100.
Munik MS, Ekmekçioğlu C (2015). Prooxidant effects of melatonin: a brief review. Turk J Biol 39: 832-839.
Ohkawa H, Ohishi N, Yagi K (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95: 351–358.
Oršolić N, Gajski G, Garaj-Vrhovac V, Dikić D, Prskalo ZŠ, Sirovina D (2011). DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice. Eur J Pharmacol 656: 110–118.
Oršolić N, Sirovina D, Gajski G, Garaj-Vrhovac V, Jembrek MJ, Kosalec I (2013). Assessment of DNA damage and lipid peroxidation in diabetic mice: effects of propolis and epigallocatechin gallate (EGCG). Mut Res 757: 36–44.
Prattichizzo F, Giuliani A, Ceka A, Rippo MR, Bonfigli AR, Testa R, Procopio AD, Olivieri F (2015). Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes. Clin Epigenetics 7: 56.
Rahimi R, Nikfar S, Larijani B, Abdollahi M (2005). A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother 59: 365–373.
Rochette L, Zeller M, Cottin Y, Vergely C (2014). Diabetes, oxidative stress and therapeutic strategies. Biochim Biophys Acta 1840: 2709–2729.
Roy S, Metya S, Sannigrahi S, Rahaman N, Ahmed F (2013). Treatment with ferulic acid to rats with streptozotocin- induced diabetes: effects on oxidative stress, pro-inflammatory cytokines, and apoptosis in the pancreatic β cell. Endocrine 44: 369–379.
Shaker ME, Houssen ME, Abo-Hashem EM, Ibrahim TM (2009). Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress. J Physiol Biochem 65: 225–233.
Singh NP, McCoy MT, Tice RR, Schneider EL (1988). A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175: 184–191.
Sudnikovich EJ, Maksimchik YZ, Zabrodskaya SV, Kubyshin VL, Lapshina EA, Bryszewska M, Reiter RJ, Zavodnik IB (2007). Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur J Pharmacol 569: 180–187.
Sun Y, Oberley LW, Li Y (1988). A simple method for clinical assay of superoxide dismutase. Clin Chem 34: 497–500.
Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007). One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42: 28–42.
Tangvarasittichai S (2015). Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 6: 456–480.
Teodoro-Morrison T, Janssen MJ, Mols J, Hendrickx BH, Velmans MH, Lotz J, Lackner K, Lennartz L, Armbruster D, Maine G et al. (2015) Evaluation of a next generation direct whole blood enzymatic assay for hemoglobin A1c on the ARCHITECT c8000 chemistry system. Clin Chem Lab Med 53: 125–132.
Tietze F (1969). Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27: 502–522.
Vural H, Sabuncu T, Arslan SO, Aksoy N (2001). Melatonin inhibits lipid peroxidation and stimulates the antioxidant status of diabetic rats. J Pineal Res 31: 193–198.
Woo J, Yeo NH, Shin KO, Lee HJ, Yoo J, Kang S (2010). Antioxidant enzyme activities and DNA damage in children with type 1 diabetes mellitus after 12 weeks of exercise. Acta Paediatr 99: 1263–1268.
Wu J, Yan LJ (2015). Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic beta cell glucotoxicity. Diabetes Metab Syndr Obes 8: 181–188.
Xu YJ, Tappia PS, Neki NS, Dhalla NS (2014). Prevention of diabetes- induced cardiovascular complications upon treatment with antioxidants. Heart Fail Rev 19: 113–121.
Zephy D, Ahmad J (2015). Type 2 diabetes mellitus: role of melatonin and oxidative stress. Diabetes Metab Syndr 9: 127–131.
Zhang HM, Zhang Y (2014). Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57: 131–146.