METOTREKSAT ARACILI NEFROTOKSİSİTEDE RAMELTEONUN KORUYUCU ETKİSİNİN DEĞERLENDİRİLMESİ

Year 2023, Volume: 30 Issue: 2, 155 - 162, 22.06.2023

Halil İbrahim Büyükbayram , Dilek Bayram , Hatice Kübra Doğan

https://doi.org/10.17343/sdutfd.1114352

Cited By: 1

Abstract

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.

Keywords

Apoptoz, İlaca bağlı nefrotoksisite, Melatonin analogları, Oksidatif stres

Supporting Institution

Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Project Number

TSG-2020-8134

EVALUATION OF THE PROTECTIVE EFFECT OF RAMELTEON IN METHOTREXATE INDUCED NEPHROTOXICITY

Abstract

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.

Keywords

Melatonin analogs, drug induced nephrotoxicity, oxidative stress, apoptosis

Project Number

TSG-2020-8134

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