.: ORİJİNAL ARAŞTIRMA
Effects of Oleuropein on Nitric Oxide, Glutathione, Malondialdehyde Levels and Glutathione Peroxidase Activities in Various Tissues of Streptozotocin-Induced Diabetic Rats Treated with Metformin and Insulin
Streptozotosin ile Diyabet Oluşturulmuş ve Metformin ile İnsülin Uygulanan Ratlarda Oleuropein'in Çeşitli Dokularda Nitrik Oksit, Glutatyon, Malondialdehit Düzeyleri ve Glutatyon Peroksidaz Aktivitesi Üzerine Etkileri
Turkiye Klinikleri J Vet Sci. 2019;10(1):1-10
doi: 10.5336/vetsci.2018-63762
Makale Dili: EN
Tam Metin
ABSTRACT
Objective: The aim of the present study was to investigate the effects of oleuropein on nitric oxide (NO) and oxidant-antioxidant levels in tissues of streptozotocin-induced diabetic rats treated with metformin and insulin. Material and Methods: A total of 40 male Sprague-Dawley rats were used in this study. Animals were divided into 5 groups (n=8) including 3 experiment and 2 control groups. Saline solution was injected intraperitoneally (IP) to the rats in control group. 50 mg/kg STZ was given IP to the Diabetic Control, 50 mg/kg streptozotocin (STZ)+100 mg/kg Metformin+4 IU/kg insulin was given IP to Group 1, 50 mg/kg STZ+100 mg/kg Metformin+4 IU/kg insulin was given IP and 30 mg/kg oleuropein was given orally to Group 2 and 50 mg/kg STZ IP and 30 mg/kg oleuropein was given orally to Group 3. Results: Metformin and insulin with oleuropein have a synergistic effect on regulatory activity of the GSH, MDA, NO levels and GSHPx activities of the kidney, brain and heart tissues. Using metformin and insulin with oleuropein increased the GSH levels of the kidney (p<0.001), brain (p<0.001) and heart tissues (p<0.05); also increased the GSHPx activity of the brain (p<0.01) and the heart tissues (p<0.001) and reduced MDA and NO levels of the kidney, brain and heart tissues (p<0.001). There were no statistically significant differences in GSHPx activity of kidney tissues of experimental groups. Conclusion: Using oleuropein, on streptozotocin-diabetics, in combination with metformin and insulin seems to have synergistic effect on the antioxidants in kidney, brain and heart tissues and effective in regulating the NO level on tissues.
Keywords: Deneysel diabetes mellitus; glutatyon; glutatyon peroksidaz; insulin; malondialdehid; metformin; nitrik oksid; oleuropein
Objective: The aim of the present study was to investigate the effects of oleuropein on nitric oxide (NO) and oxidant-antioxidant levels in tissues of streptozotocin-induced diabetic rats treated with metformin and insulin. Material and Methods: A total of 40 male Sprague-Dawley rats were used in this study. Animals were divided into 5 groups (n=8) including 3 experiment and 2 control groups. Saline solution was injected intraperitoneally (IP) to the rats in control group. 50 mg/kg STZ was given IP to the Diabetic Control, 50 mg/kg streptozotocin (STZ)+100 mg/kg Metformin+4 IU/kg insulin was given IP to Group 1, 50 mg/kg STZ+100 mg/kg Metformin+4 IU/kg insulin was given IP and 30 mg/kg oleuropein was given orally to Group 2 and 50 mg/kg STZ IP and 30 mg/kg oleuropein was given orally to Group 3. Results: Metformin and insulin with oleuropein have a synergistic effect on regulatory activity of the GSH, MDA, NO levels and GSHPx activities of the kidney, brain and heart tissues. Using metformin and insulin with oleuropein increased the GSH levels of the kidney (p<0.001), brain (p<0.001) and heart tissues (p<0.05); also increased the GSHPx activity of the brain (p<0.01) and the heart tissues (p<0.001) and reduced MDA and NO levels of the kidney, brain and heart tissues (p<0.001). There were no statistically significant differences in GSHPx activity of kidney tissues of experimental groups. Conclusion: Using oleuropein, on streptozotocin-diabetics, in combination with metformin and insulin seems to have synergistic effect on the antioxidants in kidney, brain and heart tissues and effective in regulating the NO level on tissues.
Keywords: Deneysel diabetes mellitus; glutatyon; glutatyon peroksidaz; insulin; malondialdehid; metformin; nitrik oksid; oleuropein
ÖZET
Amaç: Bu çalışmada, streptozotosin ile diyabet oluşturulmuş ve metformin ve insülin tedavisi gören ratlarda, oleuropein'in dokularda nitrik oksit (NO) ve oksidan-antioksidan düzeyleri üzerine etkilerinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmada, 40 Sprague-Dawley cinsi erkek rat 3 deney ve 2 kontrol olmak üzere, 5 gruba ayrıldı (n=8). Kontrol grubuna intraperitoneal (IP) olarak izotonik sodyum klorür çözeltisi uygulandı. Diyabetik Kontrol Grubu'na IP olarak 50 mg/kg STZ, Grup 1'e IP olarak 50 mg/kg Streptozotosin (STZ)+100 mg/kg Metformin+4 IU/kg insülin, Grup 2'ye IP olarak 50 mg/kg STZ+100 mg/kg Metformin+4 IU/kg insülin ve oral olarak 30 mg/kg oleuropein ve Grup 3'e IP olarak 50 mg/kg STZ ve oral olarak 30 mg/kg oleuropein verildi. Bulgular: Oleuropein ile birlikte metformin ve insülin kullanımının, böbrek, beyin ve kalp dokularının glutatyon (GSH), malondialdehit (MDA) ve NO düzeylerinin ve GSHPx aktivitelerinin düzenlenmesinde sinerjik bir etkiye sahip olduğu belirlendi. Oleuropein ile birlikte metformin ve insülin uygulanmasının böbrek (p<0,001), beyin (p<0,001) ve kalp dokusu (p<0,05) GSH düzeyleri ile beyin (p<0,01) ve kalp dokusu (p<0,001) GSHPx aktivitelerini arttırırken, böbrek, beyin ve kalp dokularında (p<0,001) MDA ve NO seviyelerini azalttığı belirlendi. Grupların, böbrek dokusu glutatyon peroksidaz (GPHPx) aktivitelerinde ise istatistiksel bir farklılığa rastlanmadı. Sonuç: Elde ettiğimiz veriler, streptozotosin ile diyabet oluşturulmuş ratlarda insülin ve metformin ile birlikte oleuropein uygulanmasının böbrek, beyin ve kalp dokularında antioksidan denge ve NO düzeyleri üzerinde düzenleyici aktivite gösterdiğini ortaya koymaktadır.
Anahtar Kelimeler: Experimental diabetes mellitus; glutathione; glutathione peroxidase; insulin; malondialdehyde; metformin; nitric oxide; oleuropein
Amaç: Bu çalışmada, streptozotosin ile diyabet oluşturulmuş ve metformin ve insülin tedavisi gören ratlarda, oleuropein'in dokularda nitrik oksit (NO) ve oksidan-antioksidan düzeyleri üzerine etkilerinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: Çalışmada, 40 Sprague-Dawley cinsi erkek rat 3 deney ve 2 kontrol olmak üzere, 5 gruba ayrıldı (n=8). Kontrol grubuna intraperitoneal (IP) olarak izotonik sodyum klorür çözeltisi uygulandı. Diyabetik Kontrol Grubu'na IP olarak 50 mg/kg STZ, Grup 1'e IP olarak 50 mg/kg Streptozotosin (STZ)+100 mg/kg Metformin+4 IU/kg insülin, Grup 2'ye IP olarak 50 mg/kg STZ+100 mg/kg Metformin+4 IU/kg insülin ve oral olarak 30 mg/kg oleuropein ve Grup 3'e IP olarak 50 mg/kg STZ ve oral olarak 30 mg/kg oleuropein verildi. Bulgular: Oleuropein ile birlikte metformin ve insülin kullanımının, böbrek, beyin ve kalp dokularının glutatyon (GSH), malondialdehit (MDA) ve NO düzeylerinin ve GSHPx aktivitelerinin düzenlenmesinde sinerjik bir etkiye sahip olduğu belirlendi. Oleuropein ile birlikte metformin ve insülin uygulanmasının böbrek (p<0,001), beyin (p<0,001) ve kalp dokusu (p<0,05) GSH düzeyleri ile beyin (p<0,01) ve kalp dokusu (p<0,001) GSHPx aktivitelerini arttırırken, böbrek, beyin ve kalp dokularında (p<0,001) MDA ve NO seviyelerini azalttığı belirlendi. Grupların, böbrek dokusu glutatyon peroksidaz (GPHPx) aktivitelerinde ise istatistiksel bir farklılığa rastlanmadı. Sonuç: Elde ettiğimiz veriler, streptozotosin ile diyabet oluşturulmuş ratlarda insülin ve metformin ile birlikte oleuropein uygulanmasının böbrek, beyin ve kalp dokularında antioksidan denge ve NO düzeyleri üzerinde düzenleyici aktivite gösterdiğini ortaya koymaktadır.
Anahtar Kelimeler: Experimental diabetes mellitus; glutathione; glutathione peroxidase; insulin; malondialdehyde; metformin; nitric oxide; oleuropein
REFERANSLAR:
- Halifeoğlu İ, Karataş F, Çolak R, Canatan H, Selda T. [Oxidant and antioxidant status in type 2 diabetic patients before and after therapy]. Fırat Tıp Dergisi. 2005;10(3):117-22.
- Kakkar R, Mantha SV, Radhi J, Prasad K, Kalra J. Antioxidant defense system in diabetic kidney: a time course study. Life Sci. 1997;60(9):667-79. [Crossref]
- Montes-Cortes DH, Hicks JJ, Ceballos-Reyes GM, Garcia-Sanchez JR, Medina-Navarro R, Olivares-Corichi IM. Chemical and functional changes of human insulin by in vitro incubation with blood from diabetic patients in oxidative stress. Metabolism. 2010;59(7):935-42. [Crossref] [PubMed]
- Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother. 2005;59(7):365-73. [Crossref] [PubMed]
- Maritim AC, Moore BH, Sanders RA, Watkins JB. Effects of melatonin on oxidative stress in streptozotocin-induced diabetic rats. Int J Toxicol. 1999;18(3):161-6. [Crossref]
- De La Cruz JP, Del Río S, Arrebola MM, López-Villodres JA, Jebrouni N, González-Correa JA. Effect of virgin olive oil plus acetylsalicylic acid on brain slices damage after hypoxia-reoxygenation in rats with type 1-like diabetes mellitus. Neurosci Lett. 2010;471(2):89-93. [Crossref] [PubMed]
- Milani E, Nikfar S, Khorasani R, Zamani MJ, Abdollahi M. Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats. Comp Biochem Physiol C Toxicol Pharmacol. 2005;140(2):251-5. [Crossref] [PubMed]
- Koksal M, Eren MA, Turan MN, Sabuncu T. The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients. Eur J Intern Med. 2011;22(3):249-53. [Crossref] [PubMed]
- Karabağ-Çoban F, Hazman O, Bozkurt MF, İnce S. Antioxidant status and anti-inflammatory effects of oleuropein in streptozotocin-induced diabetic nephropathy in rats. European J Med Plants. 2017;18(2):1-10. [Crossref]
- Sundaram RK, Bhaskar A, Vijayalingam S, Viswanathan M, Mohan R, Shanmugasundaram KR. Antioxidant status and lipid peroxidation in type ıı diabetes mellitus with and without complications. Clin Sci (Lond). 1996;90(4):255-60. [Crossref] [PubMed]
- Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr. 2002;76(6):1191-201. [Crossref] [PubMed]
- Huang PL, Huang PL, Lee-Huang S. Oleuropein and related compounds reduce atherosclerosis. Open Conf Proc J. 2010;1(1):81-6. [Crossref]
- Mezawa M, Takemoto M, Onishi S, Ishibashi R, Ishikawa T, Yamaga M, et al. The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors. 2012;38(6):416-21. [Crossref] [PubMed]
- Çolak S, Geyikoğlu F, Turkez H, Bakir M, Husseinigouzdaganii M, Can S, et al. The effects of lichens extracts in the healthy rats and the medical utility of these extracts in the prevention of diabetes-associated multiple organ failures. Kafkas Univ Vet Fak Derg. 2015;21(1):101-10.
- Visioli F, Poli A, Gall C. Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev. 2002;22(1):65-75. [Crossref] [PubMed]
- Ogun M, Ozcan A, Karaman M, Merhan O, Ozen H, Kukurt A, et al. Oleuropein ameliorates arsenic induced oxidative stress in mice. J Trace Elem Med Biol. 2016;36:1-6. [Crossref] [PubMed]
- Gonzalez M, Zarzuelo A, Gamez MJ, Utrilla MP, Jimenez J, Osuna I. Hypoglycemic activity of olive leaf. Planta Med. 1992;58(06):513-5. [Crossref] [PubMed]
- Al-Azzawie HF, Alhamdani MS. Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits. Life Sci. 2006;78(12):1371-7. [Crossref] [PubMed]
- Cusi K. Metformin: a review of its metabolic effects. Curr Diabetes Rev. 1998;6:89-131.
- Correia S, Carvalho C, Santos MS, Proença T, Nunes E, Duarte AI, et al. Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med Chem.2008;4(4):358-64. [Crossref] [PubMed]
- Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11(1):1-10. [Crossref] [PubMed] [PMC]
- Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux JL. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism. 2005;54(6):829-34. [Crossref] [PubMed]
- Küçükkaya B, Oztürk G, Yalçintepe L. Nitric oxide levels during erythroid differentiation in K562 cell line. Indian J Biochem Biophys. 2006;4(43):251-3.
- Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62-71. [Crossref] [PubMed]
- Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res. 1999;43(3):652-71. [Crossref]
- Öztaşan N, Bülbül A, Eryavuz A, Avcı G, Küçükkurt I, Fidan AF. Effect of Yucca schidigera extract on blood pressure, antioxidant activity and some blood parameters in the L-name-induced hypertensive rats. Ankara Üniv Vet Fak Derg. 2008;55: 149-53.
- Malinski T, Bailey F, Zhang ZG, Chopp M. Nitric oxide measured by a porphyrinic micro sensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1993;13(3): 355-8. [Crossref] [PubMed]
- Jiang MH, Kaku T, Hada J, Hayashi Y. 7-nitroindazole reduces nitric oxide concentration in rat hippocampus after transient forebrain ischemia. Eur J Pharmacol. 1999;380(2-3):117-21. [Crossref]
- Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. 1963;61:882-8.
- Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976;71(4):952-8. [Crossref]
- Yoshioka T, Kawada K, Shimada T, Mori M. Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol. 1979;135(3):372-6. [Crossref]
- Peterson GL. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977;83(2):346-56. [Crossref]
- Singh I, Mok M, Christensen AM, Turner AH, Hawley JA. The effects of polyphenols in olive leaves on platelet function. Nutr Metab Cardiovasc Dis. 2008;18(2):127-32. [Crossref] [PubMed]
- Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002; 25(12):2244-8. [Crossref] [PubMed]
- Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabet Med. 2005;22(4):497-502. [Crossref] [PubMed]
- Evans JM, Donnan PT, Morris AD. Adherence to oral hypoglycaemic agents prior to insulin therapy in type 2 diabetes. Diabet Med. 2002;19(8):685-8. [Crossref] [PubMed]
- Geyikoglu F, Emir M, Colak S, Koc K, Turkez H, Bakir M, et al. Effect of oleuropein against chemotherapy drug-induced histological changes, oxidative stress, and DNA damages in rat kidney injury. J Food Drug Anal. 2017;25(2):447-59. [Crossref] [PubMed]
- Mohagheghi F, Bigdeli MR, Rasoulian B, Zeinanloo AA, Khoshbaten A. Dietary virgin olive oil reduces blood brain barrier permeability, brain edema, and brain injury in rats subjected to ischemia-reperfusion. Scientific World Journal. 2010;10:1180-91. [Crossref] [PubMed] [PMC]
- González-Correa JA, Mu-oz-Marín J, Arrebola MM, Guerrero A, Narbona F, López-Villodres JA, et al. Dietary virgin olive oil reduces oxidative stress and cellular damage in rat brain slices subjected to hypoxia-reoxygenation. Lipids. 2007;42(10):921-9. [Crossref] [PubMed]
- Chakrabarti S, Cukiernik M, Hileeto D, Evans T, Chen S. Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy. Diabetes Metab Res Rev. 2000;16(6):393-407. [Crossref]
- Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):813-20. [Crossref] [PubMed]
- Mügge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelial-dependent vascular relaxation in cholesterol-fed rabbits. Circ Res. 1991;69(5):1293-300. [Crossref] [PubMed]
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