Melatonin Reseptor Agonisti Agomelatin'in Parasetamol ile İndüklenmiş Nefrotoksisitede Koruyucu Etkileri

Year 2019, Volume: 39 Issue: 2, 81 - 89, 01.06.2019

Nevin Tugce Kartal Aslı Ozbek-bilgin Şaziye Sezin Yücelik , Zekai Halıcı , Elif Çadırcı

Abstract

Parasetamol supraterapötik dozlarda kullanıldığında böbreklerde hasara neden olabilmektedir. Agomelatin ise melatonin reseptör analogu olan antidepresan etkili bir ilaçtır. Bu bilgiler ışığında Agomelatin’in yüksek doz parasetamol ile oluşturulan nefrotoksisite üzerine koruyucu etkisini biyokimyasal olarak belirlemeyi amaçladık. Çalışmamızda 42 adet Sprague Dawley cinsi erkek rat 7 gruba ayrıldı; Kontrol, Parasetamol (2 g/kg), NAC+Parasetamol (140 mg/kg+2 g/kg), Agomelatin+Parasetamol (20 mg/kg+2 g/kg), Agomelatin+Parasetamol (40 mg/
kg+2g/kg), Agomelatin (40 mg/kg), NAC (140 mg/kg). Parasetamol uygulamasından 24 saat sonra tüm gruplardan alınan doku ve kan örneklerinde biyokimya sal incelemeler yapıldı. Yapılan biyokimyasal incelemede, parasetamol ile nefrotoksisite oluşturulmuş grupta üre ve kreatinin değerlerinin anlamlı şekilde yükseldiği, agomelatin ile tedavi edilen gruplarda ise; üre ve kreatinin serum seviyelerinin sadece parasetamol verilen gruba göre anlamlı şekilde azaldığı tespit edildi. Bu azalış miktarı, agomelatinin farklı dozlarında değişiklik göstermedi. Doku düzeyinde yapılan değerlendirmelerde de parasetamol ile nefrotoksisite oluşturulmuş grupta GSH ve SOD seviyelerinin anlamlı olarak düştüğü ve MDA seviyesinin anlamlı şekilde yükseldiği, agomelatin ile tedavi edilen gruplarda ise; GSH ve SOD seviyesinin anlamlı olarak yükseldiği ve MDA seviyelerinin anlamlı şekilde azaldığı tespit edildi. Sonuç olarak; yüksek doz parasetamolün neden olduğu nefrotoksisitenin önlenmesinde agomelatinin tedavi edici etkisinin olduğu biyokimyasal olarak gösterildi. Bu sonuç, klinikte görülen parasetamol zehirlenmesinde agomelatin kullanılabileceği konusunda umut verici olmuştur.

Keywords

Agomelatin, böbrek, nefrotoksisite, parasetamol, rat

Supporting Institution

Atatürk Üniversitesi Bilimsel Araştırma Projeleri Birimi

Project Number

2012/76

Protective Effects of Agomelatin, a Melatonin Receptor Agonist, on Paracetamol Induced Nephrotoxicity

Abstract

Paracetamol may cause kidney damage when used in supratherapeutic doses. Agomelatine is an antidepressant drug that is a melatonin receptor analogue. In the light of this information, we aimed to determine the protective effect of Agomelatine on nephrotoxicity induced by high dose paracetamol biochemically. In our study, 42 Sprague Dawley male rats were divided into 7 group; Control, Paracetamol (2 g/kg), NAC+Paracetamol (140 mg/kg+2 g/kg), Agomelatine+Paracetamol (20 mg/kg+2 g/kg), Agomelatin+Paracetamol (40 mg/kg+2 g/kg), Agomelatine (40 mg/kg), NAC (140 mg/kg). Biochemical examinations were performed on tissue and blood samples from all groups 24 hours after paracetamol administration. In the biochemical examination, the urea and creatinine levels were significantly increased in the group induced nephrotoxicity with paracetamol, and it was determined that serum levels of urea and creatinine decreased significantly with the administration of agomelatin. This decrease did not change in different doses of agomelatine. In the evaluations made at the tissue level, in the group induced nephrotoxicity with paracetamol, GSH and SOD levels decreased significantly and MDA level increased significantly; It was determined that GSH and SOD levels increased significantly and MDA levels decreased significantly in the groups treated with agomelatine. As a result; It has been shown biochemically that agomelatine has a therapeutic effect in preventing nephrotoxicity caused by high dose paracetamol. This result was promising that agomelatine can be used in paracetamol poisoning seen in the clinic.

Keywords

Agomelatine, kidney, nephrotoxicity, paracetamol, rat

Project Number

2012/76

References

• 1. Lewis RK, Paloucek FP: Assessment and treatment of acetaminophen overdose. Clinical Pharmacology 1991, 10(10):765-774.
• 2. Spooner JB, Harvey JG: The history and usage of paracetamol. The Journal of International Medical Research 1976, 4(4 Suppl): 1-6.
• 3. Larson AM: Acetaminophen hepatotoxicity. Clinical Liver Disease 2007, 11(3):525-548.
• 4. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB: Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. Journal of Pharmacology and Experimental Therapeutics 1973, 187(1): p. 211-217.
• 5. Dahlin DC, Miwa GT, Lu AY, Nelson SD: N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proceedings of the National Academy of Sciences 1984, 81(5):1327-1331.
• 6. Hinson JA, Reid AB, McCullough SS, James LP: Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metabolism Reviews 2004, 36(3-4):805-822.
• 7. Barile AF: Clinical Toxicology Principles and Mechanisms. 2004, Boca Raton, Florida: CRC Press LLC.
• 8. Blantz RC: Acetaminophen: acute and chronic effects on renal function. American Journal of Kidney Diseases 1996, 28(1 Suppl 1), 3-6.
• 9. Dolder CR, Nelson M, Snider M: Agomelatine treatment of major depressive disorder. The Annals of Pharmacotherapy 2008, 42(12):1822-1831.
• 10. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D: The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. Journal of Pharmacology and Experimental Therapeutics 2003, 306(3): 954-964.
• 11. Guerrero JM, Reiter RJ: Melatonin-immune system relationships. Current Topics in Medicinal Chemistry 2002, 2(2):167-179.
• 12. Cos S, Fernández R, Güézmes A, Sánchez-Barceló EJ: Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Research 1998, 58:4383-4390.
• 13. Reiter RJ, The ageing pineal gland and its physiological consequences. BioEssays: news and reviews in molecular, cellular and developmental biology 1992, 14(3):169-175.
• 14. Reiter RJ, Oxidative damage in the central nervous system: protection by melatonin. Progress in Neurobiology 1998, 56(3):359-384.
• 15. Dubocovich ML: Melatonin receptors: are there multiple subtypes? Trends in Pharmacological Sciences 1995, 16(2):50-56.
• 16. Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C: Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Research 1995, 23(3):327-333.
• 17. Benitez-King G, Huerto-Delgadillo L, Anton-Tay F: Binding of 3H-melatonin to calmodulin. Life Sciences 1993, 53(3):201-207.
• 18. Reiter RJ: Antioxidant actions of melatonin. Advances in Pharmacology, 1997. 38: p. 103-17.
• 19. Sener G, Sehirli AO, Ayanoglu-Dulger G: Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study. Journal of Pineal Research 2003, 35(1):61-68.
• 20. Kanno S, Tomizawa A, Hiura T, Osanai Y, Kakuta M, Kitajima Y, Koiwai K, Ohtake T, Ujibe M, Ishikawa M: Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice. Biological & Pharmaceutical Bulletin 2006, 29(3):472-476.
• 21. Chattopadhyay RR: Possible mechanism of hepatoprotective activity of Azadirachta indica leaf extract: part II. Journal of Ethnopharmacology 2003, 89(2-3): 217-219.
• 22. Kuralay F, Akarca US, Ozütemiz AO, Kutay F, Batur Y: Possible role of glutathione in prevention of acetaminophen-induced hepatotoxicity enhanced by fish oil in male Wistar rats. Journal of Toxicology and Environmental Health, Part A 1998, 53(3):223-229.
• 23. Flanagan RJ, Meredith TJ: Use of N-acetylcysteine in clinical toxicology. American Journal of Medicine 1991: 91(3C):131S-139S.
• 24. Yayla M, Halici Z, Unal B, Bayir Y, Akpinar E, Gocer F: Protective effect of Et-1 receptor antagonist bosentan on paracetamol induced acute liver toxicity in rats. European Journal of Pharmacology 2014 Mar, 5;726:87-95.
• 25. Bektur NE, Sahin E, Baycu C, Unver G: Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice. Toxicology and Industrial Health 2016 Apr, 32(4):589-600.
• 26. Ferah I, Halici Z, Bayir Y, Demirci E, Unal B, Cadirci E: The role of infliximab on paracetamol-induced hepatotoxicity in rats. Immunopharmacology and immunotoxicology 2013, 35(3):373-81.
• 27. Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, Honma K, Kondo T: Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radical Biology&Medicine 1999, 27(7-8):838-847.
• 28. Bjorck S, Svalander CT, Aurell M, Acute renal failure after analgesic drugs including paracetamol (acetaminophen). Nephron 1988, 49(1):45-53.
• 29. Cobden I, Record CO, Ward MK, Kerr DN: Paracetamol-induced acute renal failure in the absence of fulminant liver damage. British Medical Journal 1982, 284(6308):21-22.
• 30. Cekmen M, Ilbey YO, Ozbek E, Simsek A, Somay A, Ersoz C: Curcumin prevents oxidative renal damage induced by acetaminophen in rats. Food and Chemical Toxicology 2009, 47(7):1480-1484.
• 31. Lucas AM, Hennig G, Dominick PK, Whiteley HE, Roberts JC, Cohen SD: Ribose cysteine protects against acetaminophen-induced hepatic and renal toxicity. Toxicologic Pathology 2000, 28(5):697-704.
• 32. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P: Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clinical Chemistry 1997, 43(7):1209-14.
• 33. Yapar K, Kart A, Karapehlivan M, Atakisi O, Tunca R, Erginsoy S, Citil M: Hepatoprotective effect of L-carnitine against acute acetaminophen toxicity in mice. Experimental and Toxicologic Pathology 2007, 59(2):121-128.
• 34. Hsu CC, Lin CC, Liao TS, Yin MC. Protective effect of s-allyl cysteine and s-propyl cysteine on acetaminophen-induced hepatotoxicity in mice. Food and Chemical Toxicology 2006, 44(3):393-397.
• 35. Karakus E, Halici Z, Albayrak A, Polat B, Bayir Y, Kiki I, Cadirci E, Topcu A, Aksak S: Agomelatine: An antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats. Human & Experimental Toxicology 2013 Aug, 32(8):846-857.
• 36. Zhao YL, Zhou GD, Yang HB, Wang JB, Shan LM, Li RS, Xiao XH: Rhein protects against acetaminophen-induced hepatic and renal toxicity. Food and Chemical Toxicology 2011, 49(8):1705-1710.
• 37. Atkuri KR, Mantovani JJ, Herzenberg LA: N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology 2007, 7(4):355-359.
• 38. Manda K, Bhatia AL, Role of β-carotene against acetaminophen-induced hepatotoxicity in mice. Nutrition Research 2003, 23:1097-1103.
• 39. Chularojmontri L, Wattanapitayakul SK, Herunsalee A, Charuchongkolwongse S, Niumsakul S, Srichairat S: Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Biological & Pharmaceutical Bulletin 2005; 28(7):1165-1171.
• 40. Gao H, Zhou YW: Anti-lipid peroxidation and protection of liver mitochondria against injuries by picroside II. World Journal of Gastroenterology 2005, 11(24):3671-3674.
• 41. Lei XG, Zhu JH, McClung JP, Aregullin M, Roneker CA. Mice deficient in Cu, Zn-superoxide dismutase are resistant to acetaminophen toxicity. Biochemical Journal 2006. 399(3):455-461.