Öz
Amaç
İmmünsüpresif ve antikanser olarak kullanılan Metotreksat
(MTX), böbrek dahil birçok organda ciddi toksik
yan etkilere neden olmaktadır. Mtx aracılı nefrotoksisitenin
mekanizmasında oksidatif stres üzerinden
apoptotik yolakların aktive olması yer almaktadır.
Çalışmamızda antioksidan ve antiapoptotik özellikleri
iyi bilinen melatonin’in analoglarından Ramelteon’un
(RML) MTX nefrotoksisitesindeki koruyucu etkilerini
araştırdık.
Gereç ve Yöntem
32 adet sıçan Kontrol, MTX, MTX+RML ve RML olmak
üzere 4 gruba ayrıldı. Gruplara göre 7 gün boyunca
oral gavajla salin (SF) ya da RML (10 mg/kg)
uygulandı, 2. gün ise gruplara göre intraperitoneal
20 mg MTX ya da aynı hacimde salin uygulandı. Deney
sonunda ratlar sakrifiye edilerek böbrek dokuları
Hematoksilen-Eozin (HE) boyama ile histopatolojik
olarak, caspase-3 ve TNF-α boyama ile immünohistokimyasal
(İHC) olarak incelendi. Ayrıca serum BUN,
kreatinin düzeyleri ölçüldü ve böbrek Total oksidan ve
antioksidan durum (TAS, TOS) düzeyleri çalışılarak
Oksidatif stres indeksi (OSİ) hesaplandı.
Bulgular
MTX grubunda kreatinin, TOS ve OSİ düzeyleri Kontrol
grubuna göre anlamlı düzeyde yüksek saptandı.
HE boyamada MTX grubunda Kontrol grubuna göre
anlamlı düzeyde yüksek doku hasarı, İHC boyamada
cas-3 ve TNF-α boyanma düzeylerinde artış saptandı.
Bu bulguların MTX+RML grubunda geriye çevrildiği
saptandı.
Sonuç
RML tedavisinin, MTX’in yol açtığı nefrotoksisiteye
ilişkin bulguları iyileştirdiğini gösterdik. RML, MTX
nefrotoksisitesinde umut vadeden bir ilaç olabilir.
Anahtar Kelimeler
Apoptoz İlaca bağlı nefrotoksisite Melatonin analogları Oksidatif stres
Destekleyen Kurum
Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi
Proje Numarası
TSG-2020-8134
Kaynakça
- 1. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nature reviews Rheumatology. 2020;16(3):145-54.
- 2. Gaies E, Jebabli N, Trabelsi S, Salouage I, Charfi R, Lakhal M, et al. Methotrexate side effects: review article. J Drug Metab Toxicol. 2012;3(4):1-5.
- 3. Andankar P, Shah K, Patki V. A review of drug-induced renal injury. Journal of Pediatric Critical Care. 2018;5(2):36.
- 4. Iqbal S, Armaghani A, Aiyer R, Kazory A. Methotrexate nephrotoxicity: Novel treatment, new approach. Journal of Oncology Pharmacy Practice. 2013;19(4):373-6.
- 5. Erdbrügger U, De Groot K. Is methotrexate nephrotoxic? Dose- dependency, comorbidities and comedication. Zeitschrift fur Rheumatologie. 2011;70(7):549-52.
- 6. Heidari R, Ahmadi A, Mohammadi H, Ommati MM, Azarpira N, Niknahad H. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomedicine & Pharmacotherapy. 2018;107:834-40.
- 7. Devrim E, Çetin R, Kılıçoğlu B, Imge Ergüder B, Avcı A, Durak İ. Methotrexate causes oxidative stress in rat kidney tissues. Renal failure. 2005;27(6):771-3.
- 8. Osman AT, Sharkawi SM, Hassan MI, Abo-Youssef AM, Hemeida RA. Empagliflozin and neohesperidin protect against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats. Food and Chemical Toxicology. 2021;155:112406.
- 9. Amaral FGd, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Archives of endocrinology and metabolism. 2018;62:472-9.
- 10. Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Zhou XJ, Xu B. Mitochondria: central organelles for melatonin′ s antioxidant and anti-aging actions. Molecules. 2018;23(2):509.
- 11. Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon. Nature Clinical Practice Neurology. 2007;3(4):221-8.
- 12. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical biochemistry. 2004;37(4):277-85.
- 13. Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry. 2005;38(12):1103-11.
- 14. Yanik M, Erel O, Kati M. The relationship between potency of oxidative stress and severity of depression. Acta europsychiatrica. 2004;16(4):200-3.
- 15. Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimens in cases of urinary bladder carcinoma. African Journal of Urology. 2011;17(1).
- 16. McNaughton L, Puttagunta L, Martinez-Cuesta MA, Kneteman N, Mayers I, Moqbel R, et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proceedings of the National Academy of Sciences. 2002;99(26):17161-6.
- 17. Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria- dependent and mitochondria-independent pathways of apoptosis. Archives of toxicology. 2013;87(7):1157-80.
- 18. Hempel L, Misselwitz J, Fleck C, Kentouche K, Leder C, Appenroth D, et al. Influence of high‐dose methotrexate therapy (HD‐MTX) on glomerular and tubular kidney function. Medical and Pediatric Oncology: The Official Journal of SIOP—International Society of Pediatric Oncology (Societé Internationale d'Oncologie Pédiatrique. 2003;40(6):348-54.
- 19. Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.
- 20. Mahmoud AM, Hussein OE, Abd El-Twab SM, Hozayen WG. Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and supp- ression of NF-κB/NLRP3 inflammasome axis. Food & Function. 2019;10(8):4593-607.
- 21. Zelová H, Hošek J. TNF-α signalling and inflammation: interactions between old acquaintances. Inflammation Research. 2013;62(7):641-51.
- 22. Campbell MT, Dagher P, Hile KL, Zhang H, Meldrum DR, Rink RC, et al. Tumor necrosis factor-α induces intrinsic apoptotic signaling during renal obstruction through truncated bid activation. The Journal of urology. 2008;180(6):2694-700.
- 23. Türk E, Güvenç M, Cellat M, Uyar A, Kuzu M, Ağgül AG, et al. Zingerone protects liver and kidney tissues by preventing oxidative stress, inflammation, and apoptosis in methotrexate-treated rats. Drug and Chemical Toxicology. 2020:1-12.
- 24. Ferlazzo N, Andolina G, Cannata A, Costanzo MG, Rizzo V, Currò M, et al. Is melatonin the cornucopia of the 21st century? Antioxidants. 2020;9(11):1088.
- 25. Oleshchuk O, Ivankiv Y, Falfushynska H, Mudra A, Lisnychuk N. Hepatoprotective effect of melatonin in toxic liver injury in rats. Medicina. 2019;55(6):304.
- 26. Haghi-Aminjan H, Asghari MH, Farhood B, Rahimifard M, Hashemi Goradel N, Abdollahi M. The role of melatonin on chemotherapy-induced reproductive toxicity. Journal of Pharmacy and Pharmacology. 2018;70(3):291-306.
- 27. Moradi M, Goodarzi N, Faramarzi A, Cheraghi H, Hashemian AH, Jalili C. Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis. Biomedicine & Pharmacotherapy. 2021;138:111481.
- 28. Fisher SP, Davidson K, Kulla A, Sugden D. Acute sleep‐promoting action of the melatonin agonist, ramelteon, in the rat. Journal of pineal research. 2008;45(2):125-32.
- 29. Jahovic N, Cevik H, Şehirli AÖ, Yeğen BÇ, Şener G. Melatonin prevents methotrexate‐induced hepatorenal oxidative injury in rats. Journal of pineal research. 2003;34(4):282-7.
- 30. Abraham P, Kolli VK, Rabi S. Melatonin attenuates methotrexate‐ induced oxidative stress and renal damage in rats. Cell biochemistry and function. 2010;28(5):426-33.
- 31. Oguz E, Kocarslan S, Tabur S, Sezen H, Yilmaz Z, Aksoy N. Effects of lycopene alone or combined with melatonin on methotrexate-induced nephrotoxicity in rats. Asian Pacific journal of cancer prevention. 2015;16(14):6061-6.
Öz
Objective
Methotrexate (MTX), which is used as an
immunosuppressive and anticancer drug, causes
serious toxic side effects in many organs, including
the kidney. Activation of apoptotic pathways through
oxidative stress is involved in the mechanism of MTX
mediated nephrotoxicity. In our study, we investigated
the protective effects of ramelteon (RML), an analogue
of melatonin, whose antioxidant and antiapoptotic
properties are well known, on MTX nephrotoxicity.
Material and Method
32 rats were divided into 4 groups as Control, MTX,
MTX+RML and RML. According to the groups, saline
or RML (10 mg/kg) was administered by oral gavage for
7 days, and on the 2nd day, 20 mg of MTX or the same
volume of saline was administered intraperitoneally
according to the groups. At the end of the experiment,
the rats were sacrificed and kidney tissues were
examined histopathologically with Hematoxylin-Eosin
(HE) staining and immunohistochemically (IHC) with
caspase-3 and TNF-α staining. In addition, serum BUN,
creatinine levels were measured, kidney Total Oxidant
and Antioxidant Status (TAS, TOS) levels were studied
and Oxidative Stress Index (OSI) was calculated.
Results
Creatinine, TOS and OSI levels in the MTX group
were found to be significantly higher than in the control
group. In HE staining, tissue damage was significantly
higher in MTX group compared to the control group,
and cas-3 and TNF-α staining levels were increased in
IHC staining. These findings were found to be reversed
in the MTX+RML group.
Conclusion
We show that RML treatment improves the findings of
MTX-induced nephrotoxicity. RML may be a promising
drug in MTX nephrotoxicity.
Anahtar Kelimeler
Melatonin analogs drug induced nephrotoxicity oxidative stress apoptosis
Proje Numarası
TSG-2020-8134
Kaynakça
- 1. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nature reviews Rheumatology. 2020;16(3):145-54.
- 2. Gaies E, Jebabli N, Trabelsi S, Salouage I, Charfi R, Lakhal M, et al. Methotrexate side effects: review article. J Drug Metab Toxicol. 2012;3(4):1-5.
- 3. Andankar P, Shah K, Patki V. A review of drug-induced renal injury. Journal of Pediatric Critical Care. 2018;5(2):36.
- 4. Iqbal S, Armaghani A, Aiyer R, Kazory A. Methotrexate nephrotoxicity: Novel treatment, new approach. Journal of Oncology Pharmacy Practice. 2013;19(4):373-6.
- 5. Erdbrügger U, De Groot K. Is methotrexate nephrotoxic? Dose- dependency, comorbidities and comedication. Zeitschrift fur Rheumatologie. 2011;70(7):549-52.
- 6. Heidari R, Ahmadi A, Mohammadi H, Ommati MM, Azarpira N, Niknahad H. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomedicine & Pharmacotherapy. 2018;107:834-40.
- 7. Devrim E, Çetin R, Kılıçoğlu B, Imge Ergüder B, Avcı A, Durak İ. Methotrexate causes oxidative stress in rat kidney tissues. Renal failure. 2005;27(6):771-3.
- 8. Osman AT, Sharkawi SM, Hassan MI, Abo-Youssef AM, Hemeida RA. Empagliflozin and neohesperidin protect against methotrexate-induced renal toxicity via suppression of oxidative stress and inflammation in male rats. Food and Chemical Toxicology. 2021;155:112406.
- 9. Amaral FGd, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Archives of endocrinology and metabolism. 2018;62:472-9.
- 10. Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Zhou XJ, Xu B. Mitochondria: central organelles for melatonin′ s antioxidant and anti-aging actions. Molecules. 2018;23(2):509.
- 11. Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon. Nature Clinical Practice Neurology. 2007;3(4):221-8.
- 12. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical biochemistry. 2004;37(4):277-85.
- 13. Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry. 2005;38(12):1103-11.
- 14. Yanik M, Erel O, Kati M. The relationship between potency of oxidative stress and severity of depression. Acta europsychiatrica. 2004;16(4):200-3.
- 15. Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimens in cases of urinary bladder carcinoma. African Journal of Urology. 2011;17(1).
- 16. McNaughton L, Puttagunta L, Martinez-Cuesta MA, Kneteman N, Mayers I, Moqbel R, et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proceedings of the National Academy of Sciences. 2002;99(26):17161-6.
- 17. Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria- dependent and mitochondria-independent pathways of apoptosis. Archives of toxicology. 2013;87(7):1157-80.
- 18. Hempel L, Misselwitz J, Fleck C, Kentouche K, Leder C, Appenroth D, et al. Influence of high‐dose methotrexate therapy (HD‐MTX) on glomerular and tubular kidney function. Medical and Pediatric Oncology: The Official Journal of SIOP—International Society of Pediatric Oncology (Societé Internationale d'Oncologie Pédiatrique. 2003;40(6):348-54.
- 19. Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.
- 20. Mahmoud AM, Hussein OE, Abd El-Twab SM, Hozayen WG. Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and supp- ression of NF-κB/NLRP3 inflammasome axis. Food & Function. 2019;10(8):4593-607.
- 21. Zelová H, Hošek J. TNF-α signalling and inflammation: interactions between old acquaintances. Inflammation Research. 2013;62(7):641-51.
- 22. Campbell MT, Dagher P, Hile KL, Zhang H, Meldrum DR, Rink RC, et al. Tumor necrosis factor-α induces intrinsic apoptotic signaling during renal obstruction through truncated bid activation. The Journal of urology. 2008;180(6):2694-700.
- 23. Türk E, Güvenç M, Cellat M, Uyar A, Kuzu M, Ağgül AG, et al. Zingerone protects liver and kidney tissues by preventing oxidative stress, inflammation, and apoptosis in methotrexate-treated rats. Drug and Chemical Toxicology. 2020:1-12.
- 24. Ferlazzo N, Andolina G, Cannata A, Costanzo MG, Rizzo V, Currò M, et al. Is melatonin the cornucopia of the 21st century? Antioxidants. 2020;9(11):1088.
- 25. Oleshchuk O, Ivankiv Y, Falfushynska H, Mudra A, Lisnychuk N. Hepatoprotective effect of melatonin in toxic liver injury in rats. Medicina. 2019;55(6):304.
- 26. Haghi-Aminjan H, Asghari MH, Farhood B, Rahimifard M, Hashemi Goradel N, Abdollahi M. The role of melatonin on chemotherapy-induced reproductive toxicity. Journal of Pharmacy and Pharmacology. 2018;70(3):291-306.
- 27. Moradi M, Goodarzi N, Faramarzi A, Cheraghi H, Hashemian AH, Jalili C. Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis. Biomedicine & Pharmacotherapy. 2021;138:111481.
- 28. Fisher SP, Davidson K, Kulla A, Sugden D. Acute sleep‐promoting action of the melatonin agonist, ramelteon, in the rat. Journal of pineal research. 2008;45(2):125-32.
- 29. Jahovic N, Cevik H, Şehirli AÖ, Yeğen BÇ, Şener G. Melatonin prevents methotrexate‐induced hepatorenal oxidative injury in rats. Journal of pineal research. 2003;34(4):282-7.
- 30. Abraham P, Kolli VK, Rabi S. Melatonin attenuates methotrexate‐ induced oxidative stress and renal damage in rats. Cell biochemistry and function. 2010;28(5):426-33.
- 31. Oguz E, Kocarslan S, Tabur S, Sezen H, Yilmaz Z, Aksoy N. Effects of lycopene alone or combined with melatonin on methotrexate-induced nephrotoxicity in rats. Asian Pacific journal of cancer prevention. 2015;16(14):6061-6.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Proje Numarası | TSG-2020-8134 |
| Yayımlanma Tarihi | 22 Haziran 2023 |
| Gönderilme Tarihi | 11 Mayıs 2022 |
| Kabul Tarihi | 6 Aralık 2022 |
| Yayımlandığı Sayı | Yıl 2023 Cilt: 30 Sayı: 2 |
Cited By
Ameliorative effects of topical ramelteon on imiquimod-induced psoriasiform inflammation in mice
Naunyn-Schmiedeberg's Archives of Pharmacology
https://doi.org/10.1007/s00210-024-03017-7
Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi/Medical Journal of Süleyman Demirel University is licensed under Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International.