Vankomisin kaynaklı nefrotoksisiteyi önlemede melatoninin etkinliği: deneysel bir çalışma

Year 2022, Volume: 47 Issue: 3, 1105 - 1113, 30.09.2022

Özlem Öz Gergin , Özge Cengiz Mat , Demet Bolat , Merve Kabadayı , Sibel Seçkin Pehlivan , Gülfidan Coşkun

https://doi.org/10.17826/cumj.1103876

Abstract

Amaç: Bu çalışmanın amacı, vankomisinin böbrek üzerindeki olası toksik etkilerinin belirlenmesi ve melatoninin olası koruyucu etkilerini araştırmaktır.
Gereç ve Yöntem: Bu çalışmada, sıçanlar rastgele 4 gruba ayrıldı: kontrol grubu, melatonin (10 mg/kg/gün) grubu, vankomisin uygulanan (200 mg/kg) grup ve vankomisin (200 mg/kg) +melatonin (10 mg/kg/gün) grubu. Tedavi grubundaki sıçanlara art arda yedi gün boyunca günde iki kez vankomisin ve ardından yedi gün boyunca günde bir kez melatonin (10 mg/kg/gün) verildi. Her grupta yedi sıçan yer aldı ve deneye 15 gün devam edildi. Deneyden 15 gün sonra, sıçanlar anestezi altında sakrifiye edildi. Sıçanlara ait böbrek dokuları alındı ve patolojik şiddeti değerlendirmek TNF-α ekspresyon analizi, hematoksilin ve eozin (H&E), Masson's tricrom ve Periodic acid schiff (PAS) gibi histolojik analizler yapıldı. Ek olarak, apoptozu değerlendirmek için Terminal deoksinükleotidil transferaz dUTP nick-end etiketlemesi (TUNEL) yöntemi uygulandı.
Bulgular: Vankomisin, TNF-α ekspresyonunu yükseltirken; melatonin, TNF-α immünoreaktivite yoğunluğunu azalttı ve sıçanların böbreklerinde açıkça patolojik şiddeti iyileştirdi. Ayrıca melatonin, vankomisinin neden olduğu TUNEL pozitif hücre sayılarını önemli ölçüde inhibe etti.
Sonuç: Bulgularımız, melatoninin organ koruma süresi boyunca böbreklerde vankomisinin neden olduğu proinflamatuar ve proapoptotik etkilere karşı koruyucu ve böbrek fonksiyonlarını iyileştirici etkiye sahip olduğunu gösterdi.

Keywords

Kidney damage, apoptosis, pro-inflammatory, melatonin, oxidative stress, vancomycin

Effectiveness of melatonin in preventing vancomycin-induced nephrotoxicity: an experimental study

Abstract

Purpose: The aim of the study explores probable toxic effects of vancomycin on kidney and analysis of the probable protective effects of melatonin.
Materials and Methods: In this study, rats were randomly divided into 4 groups: the control group; the melatonin (10 mg/kg/day) group; the vancomycin-treated (200 mg/kg) group; and the vancomycin (200 mg/kg) + melatonin (10 mg/kg/day) group. Rats in the treatment group were given two doses of vancomycin a day with an interval of seven consecutive days and melatonin (10 mg/kg/day) once daily for seven consecutive days. The experiment was continued for 15 days. In each group, seven rats were grouped together. 15 days after the experiment, the rats were sacrificed under anesthesia and among all groups. Kidney tissues were collected and processed for further TNF- expression analysis, as well as histological analyses such as hematoxylin and eosin (H&E), Masson's tricrom, and Periodic acid schiff (PAS) staining to assess pathological severity. In addition, a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to evaluate apoptosis.
Results: While vancomycin upregulated TNF-α expression, melatonin reduced levels of TNF-α immunoreactivity intensity and clearly improved pathological severity in rat kidneys. Further, melatonin significantly inhibited vancomycin-induced TUNEL-positive cell numbers.
Conclusion: Melatonin has protective activity against vancomycin-induced pro-inflammatory and proapoptotic effects in kidneys during organ preservation time and improves kidney function.

Keywords

Kidney damage, apoptosis, pro-inflammatory cytokines, melatonin, vancomycin

References

• 1. Basarslan F, Yilmaz N, Ates S, Ozgur T, Tutanc M, Motor VK, et al. Protective effects of thymoquinone on vancomycin-induced nephrotoxicity in rats. Hum Exp Toxicol. 2012;31:726–733.
• 2. Humanes B, Jado JC, Camano S, López-Parra V, Torres AM, Álvarez-Sala LA, et al. Protective effects of cilastatin against vancomycin-induced nephrotoxicity. Biomed Res Int. 2015;2015:704382.
• 3. Álvarez R, López Cortés LE, Molina J, Cisneros JM, Pachón J. Optimizing the clinical use of vancomycin. Antimicrob Agents Chemother. 2016;60(5):2601–2609.
• 4. Martin JH, Norris R, Barras M, Roberts J, Morris R, Doogue M, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of health-system pharmacists, the infectious diseases society of America, and the society of infectious diseases pharmacists. Clin Biochem Rev. 2010;31:21–24.
• 5. Van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity asso- ciated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013; 57:734–744.
• 6. Arimura Y, Yano T, Hirano M, Sakamoto Y, Egashira N, Oishi R. Mitochondrial superoxide production contributes to vanco- mycin-induced renal tubular cell apoptosis. Free Radic Biol Med. 2012; 52:1865–1873.
• 7. Gupta A, Biyani M, Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med. 2011;6:379–383.
• 8. Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther. 2017;102:459–469.
• 9. Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: One of evolution's best ideas. Cell Mol Life Sci. 2017;74:3863-3881.
• 10. Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes. J Pineal Res. 2013;54:127-138.
• 11. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61:253–78.
• 12. Tahan V, Atug O, Akin H, Eren F, Tahan G, Tarcin O, et al. Melatonin ameliorates methionine‐ and choline‐deficient diet‐induced nonalcoholic steatohepatitis in rats. J Pineal Res. 2009;46:401‐407.
• 13. Uckun Z, Guzel S, Canacankatan N, Yalaza C, Kibar D, Coskun Yilmaz B. Potential protective effects of naringenin against van- comycin-induced nephrotoxicity via reduction on apoptotic and oxidative stress markers in rats. Drug Chem Toxicol. 2020;43:104-111.
• 14. Keskin-Aktan A, Akbulut KG, Yazici-Mutlu Ç, Sonugur G, Ocal M, Akbulut H. The effects of melatonin and curcumin on the expression of SIRT2, Bcl-2 and Bax in the hippocampus of adult rats. Brain Res Bull. 2018;137:306–310.
• 15. Han YS, Kim SM, Lee JH, Jung SK, Noh H, Lee SH. Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrP(C) -dependent enhancement of the mitochondrial function. J Pineal Res. 2019;66:e12535.
• 16. Mercantepe F, Mercantepe T, Topcu A, Yılmaz A, Tumkaya L. Protective effects of amifostine, curcumin, and melatonin against cisplatin-induced acute kidney injury. Naunyn Schmiedebergs Arch Pharmacol. 2018;391:915-931.
• 17. Potić M, Ignjatović I, Ničković VP, Živković JB, Krdžić JD, Mitić JS, et al. Two different mela- tonin treatment regimens prevent an increase in kidney injury marker-induced by carbon tetrachloride in rat kidneys. Can J Physiol Pharmacol. 2019;97:422-428.
• 18. Kobroob A, Peerapanyasut W, Chattipakorn N, Wongmekiat O. Damaging effects of bisphenol a on the kidney and the protec- tion by melatonin: emerging evidences from in vivo and in vitro studies. Oxid Med Cell Longev. 2018; 2018:3082438.
• 19. Opie LH, Lecour S. Melatonin has multiorgan effects. Eur Heart J Cardiovasc Pharmacother. 2016;2:258–265.
• 20. Bayram A, Erkan GN, Talih G, Baskol G, Deniz K, Yildiz K, et al. The alpha-2 receptor agonist dexmedetomidine attenuates vancomycin‑induced acute kidney injury. Bratisl Lek Listy. 2019;120:429-433.
• 21. Umstätter F, Domhan C, Hertlein T, Ohlsen K, Mühlberg E, Kleist C, et al. Vancomycin resistance is overcome by conjugation of polycationic peptides. Angew Chem Int Ed Engl. 2020;59:8823-8827.
• 22. Marvin JL, Levine BJ, Papas M, Rosini JM. An evaluation of the incidence of nephrotoxicity after a loading dose of vancomycin in patients with severe renal impairment. J Emerg Med. 2019;56:701-708.
• 23. Sabler IM, Berkovitch M, Sandbank J, Kozer E, Dagan Z, Goldman M, et al. Exposure to hyperbaric oxygen intensified vancomycin-induced nephrotoxicity in rats. PLoS One. 2016;11:e0152554.
• 24. Brewer MS. Natural antioxidants: sources, compounds, mechanisms of action, and potential applications. Comprehensive Reviews in Food Science and Food Safety. 2011. vol. 10, no. 4, pp. 221–247.
• 25. Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Zhou XJ, Xu B. Mitochondria: central organelles for melatoninʼs antioxidant and anti-aging actions. Molecules. 2018;23:509.
• 26. Cai J, Yang J, Chen X, Zhang H, Zhu Y, Liu Q, et al. Melatonin ameliorates trimethyltin chloride-induced cardiotoxicity: the role of nuclear xenobiotic metabolism and Keap1-Nrf2/ARE axis-mediated pyroptosis. Biofactors. 2022;48:481-497.
• 27. Liu XJ, Wang YQ, Shang SQ, Xu S, Guo M. TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome. Ecotoxicol. Environ. Saf. 2022;230:113167.
• 28. Hardeland R. Aging, melatonin, and the pro- and anti-inflam- matory networks. Int J Mol Sci. 2019;20:1223.
• 29. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, et al. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020;10:1211.
• 30. Dutta S, Saha S, Mahalanobish S, Sadhukhan P, Sil PC. Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice. Food Chem Toxicol. 2018;118:303–316.
• 31. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int J Endocrinol. 2017; 2017:1835195.
• 32. D’Angelo G, Chimenz R, Reiter RJ, Gitto E. Use of melatonin in oxidative stress related neonatal diseases. Antioxidants (basel). 2020; 9:477. 33. Li J, Zhang W, Zhou P, Tong X, Guo D, Lin H. Selenium deficiency induced apoptosis via mitochondrial pathway caused by Oxidative Stress in porcine gastric tissues. Res. Vet. Sci. 2022;144:142-148.
• 34. Wang Z, Wu J, Hu Z, Luo C, Wang P, Zhang Y, et al. Dexmedetomidine alleviates lipopolysaccharide-induced acute kidney injury by inhibiting p75NTR-mediated oxidative stress and apoptosis. Oxid. Med. Cell. Longev. 2020;2020:5454210.
• 35. Yingjie K, Haihong Y, Lingwei C, Sen Z, Yuanting D, Shasha C, et al. Apoptosis repressor with caspase recruitment domain deficiency accelerates ischemia/reperfusion (I/R)-induced acute kidney injury by suppressing inflammation and apoptosis: the role of AKT/mTOR signaling. Biomed. Pharmacother. 2019;112:108681.
• 36. Nduhirabandi F, Lamont K, Albertyn Z, Opie LH, Lecour S. Role of toll-like receptor 4 in melatonin-induced cardioprotection. J Pineal Res. 2016;60:39–47.
• 37. Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, et al. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 2015; 11:1037–1051.
• 38. Rodriguez C, Martín V, Herrera F, García-Santos G, Rodriguez-Blanco J, Casado-Zapico S, Sánchez-Sánchez AM, et al. Mechanisms involved in the pro-apoptotic effect of melatonin in cancer cells. Int J Mol Sci. 2013;14:6597–613.
• 39. Negoescu A, Guillermet C, Lorimier P, Brambilla E, Labat-Moleur F. Importance of DNA fragmentation in apoptosis with regard to TUNEL specificity. Biomed Pharmacother. 1998;52:252–8.
• 40. Leibowitz A, Volkov A, Voloshin K, Shemesh C, Barshack I, Grossman E. Melatonin prevents kidney injury in a high salt diet-induced hypertension model by decreasing oxidative stress. J Pineal Res.2016; 60:48-54.
• 41. Shi S, Lei S, Tang C, Wang K, Xia Z. Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by acti- vation of the SIRT/Nrf!/HO-signaling pathway. Biosci Rep. 2019;39: BSR20181614.