The Effect of Melatonin on Some Coagulation Parameters in Streptozotocin-induced Diabetic Rats

Abstract

The aim of this study is to evaluate the possible protective effects of melatonin on hemostatic parameters in diabetic rats. For this purpose, 32 adult, male, healthy Wistar Abino rats were seperated into four groups. Control group didn’t exposure any trial. Melatonin group was treated with 50 mg/kg melatonin by intraperitoneally during 8 weeks. In diabetes group, diabetes was induced by subcutaneous injections of streptozotocin at dose of 40 mg/kg for two days as a single daily dose. Diabetes+Melatonin group was consist of the animals that treated with 50 mg/kg melatonin by intraperitoneally to streptozotocin induced diabetic during 8 weeks. In diabetic rats, the platelet count and fibrinogen level significantly increased compared to control group (p<0.05), whereas melatonin application to the diabetic rats caused to decrease in fibrinogen level when compared to diabetic rats (p<0.05). Activated Partial Tromboplastin Time (APTT), Prothrombin Time (PT) and International Normalized Ratio (INR) levels significantly shortened in the experimentally diabetes group compared to the control group (p<0.05). PT and INR significantly prolonged in diabetic rats with the melatonin treatment compared to diabetic rats (p<0.05). In conclusion, the obtained data indicated that administration of melatonin partly ameliorated procoagulant state caused by diabetes in rats. 

Keywords

• melatonin,APTT,fibrinogen,diabetes,rat

Streptozotosin ile Diyabet Oluşturulan Ratlarda Melatonin Uygulamasının Bazı Koagulasyon Parametreleri Üzerindeki Etkisi

Abstract

Bu çalışmanın amacı streptozotosin ile diyabet oluşturulan ratlarda hemostatik parametreler üzerine melatoninin muhtemel koruyucu etkilerinin belirlenmesidir. Bu amaçla 32 yetişkin erkek sağlıklı Wistar Abino rat dört gruba ayrıldı. Kontrol grubuna herhangi bir uygulama yapılmadı. Melatonin grubuna 8 hafta boyunca intraperitoneal olarak 50 mg/kg melatonin uygulandı. Diyabet grubunda 40 mg/kg streptozotosinin günlük tek doz olmak üzere iki gün subkutan enjeksiyonuyla diyabet oluşturuldu. Diyabet+Melatonin grubuna streptozotosin uygulanarak diyabet oluşturulduktan sonra 8 hafta boyunca intraperitoneal olarak 50 mg/kg melatonin enjekte edildi. Diyabetik ratlarda platelet sayısı ve fibrinojen seviyesi kontrol grubuna göre önemli oranda artarken (p<0.05), diyabetik ratlara melatonin uygulaması diyabet grubuna göre fibrinojen düzeyinde azalmaya neden oldu (p<0.05). Deneysel diyabet grubundaki APTT, PT ve INR düzeyleri kontrol grubuna göre önemli bir şekilde azaldı (p<0.05). Diyabetik ratlara intraperitoneal olarak melatonin uygulaması ile PT ve INR düzeyleri diyabetik ratlara göre önemli bir şekilde uzadı (p<0.05). Sonuç olarak, bu çalışmadan elde edilen veriler melatonin uygulamasının ratlarda diyabetten kaynaklanan prokoagulan durumu kısmen düzelttiğini göstermektedir.

Keywords

• melatonin,APTT,fibrinojen,diyabet,rat

References

1. American Diabetic Association. National Diabetes Fact Sheet 2011 (released Jan. 26, 2011). http://www.diabetes.org/diabetes-basics/diabetes-statistics; Last accessed date: 10.09. 2012.
2. Ashy NI, Shroff KV. Evaluation of the potential drug interaction of melatonin and warfarin: a case series. Life Sci J. 2016; 13(6):46-51.
3. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002; 287(19):2570-2581.
4. Bharti VK, Srivastava RS. Pineal proteins upregulate specific antioxidant defense systems in the brain. Oxid Med Cell Longev. 2009; 2(2):88-92.
5. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine. 2005; 27(2):189-200.
6. Castellino FJ, Ploplis VA. The protein C pathway and pathologic processes. J Thromb Haemost. 2009; 7(1):140-145.
7. Ceriello A, Taboga C, Giacomello R, Falleti E, De Stasio G, Motz E, Lizzio S, Gonano F, Bartoli E. Fibrinogen plasma levels as a marker of thrombin activation in diabetes. Diabetes. 1994; 43(3):430-432.
8. Cho YI, Mooney MP, Cho DJ. Hemorheological disorders in diabetes mellitus. J Diabetes Sci Technol. 2008; 2(6):1130-1138.

9. Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005; 9(1):11-24.
10. Creager MA, Lüscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003; 108(12):1527-1532.
11. Dahm A, Osterud B, Hjeltnes N, Sandset PM, Iversen PO. Opposite circadian rhythms in melatonin and tissue factor pathway inhibitor type 1: does daylight affect coagulation?. J Thromb Haemost. 2006; 4(8):1840-1842.
12. Dunn EJ, Ariëns RA. Fibrinogen and fibrin clot structure in diabetes. Herz. 2004; 29(5):470-479.
13. ElGendy AA, Abbas AM. Effects of warfarin and L-carnitine on hemostatic function and oxidative stress in streptozotocin-induced diabetic rats. J Physiol Biochem. 2014; 70(2):535-546.
14. Eriksson M, Carlberg B, Eliasson M. The disparity in long-term survival after a first stroke in patients with and without diabetes persists: the Northern Sweden MONICA study. Cerebrovasc Dis. 2012; 34(2):153-160.
15. Favaro E, Miceli I, Bussolati B, Schmitt-Ney M, Cavallo Perin P, Camussi G, Zanone MM. Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells: effects of pravastatin on the Akt survival pathway. Am J Pathol. 2008; 173(2):442-450.
16. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet ther¬apy in acute coronary syndrome. Circulation. 2011; 123(7):798-813.
17. Ferreiro JL, Gómez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res. 2010; 7(4):251-259.
18. Follenius M, Weibel L, Brandenberger G. Distinct modes of melatonin secretion in normal men. J Pineal Res. 1995; 18(3):135-140.
19. Ho FM, Liu SH, Liau CS, Huang PJ, Lin-Shiau SY. High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH(2)-terminal kinase and caspase-3. Circulation. 2000; 101(22):2618-2624.
20. Ido Y, Carling D, Ruderman N. Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes. 2002; 51(1):159-167.
21. Jou MJ, Peng TI, Yu PZ, Jou SB, Reiter RJ, Chen JY, Wu HY, Chen CC, Hsu LF. Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis. J Pineal Res. 2007; 43(4):389-403.
22. Kakouros N, Rade JJ, Kourliouros A, Resar JR. Platelet function in patients with diabetes mellitus: from a theoretical to a practical perspective. Int J Endocrinol. 2011; Article ID 742719:1-14. doi:10.1155/2011/742719.
23. Korish AA, Abdel Gader AGM, Alhaider AA. Camel milk ameliorates the coagulopathy in streptozotocin diabetic rat model. Int J Dairy Technol. 2015; 68(1):79-87.
24. Kostovski E, Dahm AE, Iversen N, Hjeltnes N, Østerud B, Sandset PM, Iversen PO. Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium. Blood Coagul Fibrinolysis. 2011; 22(4):254-259.
25. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004; 53(1):195-199.
26. Minneman KP, Wurtman RJ. The pharmacology of the pineal gland. Annu Rev Pharmacol Toxicol. 1976; 16:33-51.
27. Montagnana M, Salvagno GL, Lippi G. Circadian variation within hemostasis: an under recognized link between biology and disease?. Semin Thromb Hemost. 2009; 35(1):23-33.
28. Ohaeri OC, Adoga GI. Anticoagulant modulation of blood cells and platelet reactivity by garlic oil in experimental diabetes mellitus. Biosci Rep. 2006; 26(1):1-6.
29. Osende JI, Badimon JJ, Fuster V, Herson P, Rabito P, Vidhun R, Zaman A, Rodriguez OJ, Lev EI, Rauch U, Heflt G, Fallon JT, Crandall JP. Blood thrombogenic¬ity in type 2 diabetes mellitus patients is associated with gly¬cemic control. J Am Coll Cardiol. 2001; 38(5):1307-1312.
30. Pashalieva I, Decheva L, Stancheva E, Nyagolov Y, Negrev N. Melatonin and luzindole-induced effects on integral blood coagulation parameters in rats. Compt Rend Acad Bulg Sci. 2014; 67(9):1269-1274.
31. Pinotti M, Bertolucci C, Portaluppi F, Colognesi I, Frigato E, Foà A, Bernardi F. Daily and circadian rhythms of tissue factor pathway inhibitor and factor VII activity. Arterioscler Thromb Vasc Biol. 2005; 25(3):646-649.
32. Reiter RJ, Li K, Gonzalez-Brito A, Tannenbaum MG, Vaughan MK, Vaughan GM, Villanua MA. Elevated environmental temperature alters the responses of the reproductive and thyroid axes of female Syrian hamsters to afternoon melatonin injections. J Pineal Res. 1988; 5(3):301-315.
33. Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res. 2006; 41(3):288-295.
34. Rodella LF, Favero G, Foglio E, Rossini C, Castrezzati S, Lonati C, Rezzani R. Vascular endothelial cells and dysfunctions: role of melatonin. Front Biosci (Elite Ed). 2013; 5:119-129.
35. Sanz G, Fuster V. Polypill and global cardiovascular health strategies. Semin Thorac Cardiovasc Surg. 2011; 23(1):24-29.
36. Schäfer A, Fraccarollo D, Vogt C, Flierl U, Hemberger M, Tas P, Ertl G, Bauersachs J. Improved endothelial function and reduced platelet activation by chronic HMG-CoA-reductase inhibition with rosuvastatin in rats with streptozotocin-induced diabetes mellitus. Biochem Pharmacol. 2007; 73(9):1367-1375.
37. Schalkwijk CG, Poland DC, van Dijk W, Kok A, Emeis JJ, Dräger AM, Doni A, van Hinsbergh VW, Stehouwer CD. Plasma concentration of C-reactive protein is increased in type 1 diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation. Diabetologia. 1999; 42(3):351-357.
38. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87(1):4-14.
39. Stancheva E, Zarkova A, Pashalieva I, Nyagolov Y, Negrev N. Melatonin inhibits the protein C anticoagulant pathway in rats. Scr Sci Med. 2015; 47(1):57-63.
40. Tai SH, Chen HY, Lee EJ, Chen TY, Lin HW, Hung YC, Huang SY, Chen YH, Lee WT, Wu TS. Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. J Pineal Res. 2010; 49(4):332-341.
41. Takada Y, Urano T, Watanabe I, Taminato A, Yoshimi T, Takada A. Changes in fibrinolytic parameters in male patients with type 2 (non-insulin-dependent) diabetes mel¬litus. Thromb Res. 1993; 71(5):405-415.
42. Tunali T, Sener G, Yarat A, Emekli N. Melatonin reduces oxidative damage to skin and normalizes blood coagulation in a rat model of thermal injury. Life Sci. 2005; 76(11):1259-1265.
43. Vaidyula VR, Boden G, Rao AK. Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects. Platelets. 2006a; 17(8):577-585.
44. Vaidyula VR, Rao AK, Mozzoli M, Homko C, Cheung P, Boden G. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes. 2006b; 55(1):202-208.
45. Wilkinson IB, MacCallum H, Rooijmans DF, Murray GD, Cockcroft JR, McKnight JA, Webb DJ. Increased augmentation index and systolic stress in type 1 diabetes mellitus. QJM. 2000; 93(7):441-448.
46. Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, von Känel R. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. 2008; 44(2):127-133.
47. Yeom E, Byeon H, Lee SJ. Effect of diabetic duration on hemorheological properties and platelet aggregation in streptozotocin-induced diabetic rats. Sci Rep. 2016; 6:21913. doi: 10.1038/srep21913.