PROTECTIVE EFFECT OF THE RAMELTEON, A MELATONIN AGONIST, AGAINST METHOTREXATE-INDUCED BONE-TOXICITY

Year 2022, , 53 - 58, 01.03.2022

Recep Dinçer , Tuba Baykal , Duygu Kumbul Doğuç , Emine Sarman , Devran Ceylan

https://doi.org/10.17343/sdutfd.979473

Abstract

Objective
Methotrexate (MTX) used anti-metabolite, causes
bone morbidity, including growth arrest and reduced
bone mineral density. Melatonin, produced by the
pineal gland, has also multiple positive effects in human
bone cells, and positive effects on bone. Ramelteon
(RMT) is a non-selective melatonin receptor agonist.
In this study, we investigated whether ramelteon, a
melatonin agonist, has a protective effect on MTXinduced
bone toxicity.
Material and Methods
The rats divided into 4 groups, including Group 1
control group; Group 2 MTX group (20 mg/kg); Group
3 MTX+RMT (20 mg/kg + 10 mg/kg); Group 4 RMT (10
mg/kg). Oral ramelteon and intraperitoneal mtx were
applied to the rats on the second day according to
the groups. After 7 days, long bones were evaluated
histologically with hematoxylin-eosin (HE) staining and
immunohistochemically with Catepsin K and RUN X2
staining. For statistical analysis immunohistochemical
scores of the groups were compared between the
groups for this purpose, the Oneway ANOVA Duncan
test was used by SPSS-22.00 package program.
Results
There was no significant difference between the
control group (group I) and the experimental groups
(group II-group III-group IV) in H&E staining of bone
tissue sections (p>0.05). No positive staining was
observed in any of the groups in CAT-K and RUN-X
immunostaining (p>0.05).
Conclusion
It was showed that ramelteon has no anabolic
function in bone turnover, histopathological and
immunohistochemical, in bone toxicity induced by
high-dose methotrexate on intact bone tissue.

Keywords

METHOTREXATE, RAMELTEON, MELATONIN, RUNX2, Catepsin K

Supporting Institution

SDU BAP

Project Number

TSG-2020-8134

Thanks

Shedding light on this project with his pioneering ideas, I would like to thank to Prof. Hasan Yasan and Dr. Meltem Ozgocmen.

MELATONİN AGONİSTİ OLAN RAMELTEONUN METOTREKSAT KAYNAKLI KEMİK TOKSİSİTESİNE KARŞI KORUYUCU ETKİSİ

Abstract

Amaç
Metotreksat (MTX) büyüme durması ve kemik mineral
yoğunluğunun azalması dahil olmak üzere kemik
morbiditesine neden olan anti-metabolittir. Epifiz bezi
tarafından üretilen melatonin, insan kemik hücrelerinde
de birçok olumlu etkiye ve kemik üzerinde olumlu
etkilere sahiptir. Ramelteon (RMT), seçici olmayan
bir melatonin reseptör agonistidir. Bu çalışmada, bir
melatonin agonisti olan ramelteonun MTX kaynaklı
kemik toksisitesi üzerinde koruyucu bir etkisinin olup
olmadığını araştırdık.
Gereç ve Yöntem
Sıçanlar Grup 1 kontrol grubu olmak üzere 4 gruba ayrıldı;
Grup 2 MTX grubu (20 mg/kg); Grup 3 MTX+RMT
(20 mg/kg + 10 mg/kg); Grup 4 RMT (10 mg/kg).
Ratlara gruplara göre ikinci gün oral ramelteon ve
intraperitoneal mtx uygulandı. 7 gün sonra uzun kemikler
hematoksilen-eozin (HE) boyama ile histolojik
olarak ve Catepsin K ve RUN X2 boyama ile immünohistokimyasal
olarak değerlendirildi. İstatistiksel analiz
için grupların immünhistokimyasal skorları gruplar
arasında karşılaştırıldı, bu amaçla SPSS-22.00 paket
programı ile Oneway ANOVA Duncan testi kullanıldı.
Bulgular
Kemik doku kesitlerinin H&E boyamasında kontrol
grubu (grup I) ile deney grupları (grup II-grup III-grup
IV) arasında anlamlı bir fark yoktu (p>0.05). CAT-K
ve RUN-X immün boyamasında grupların hiçbirinde
pozitif boyanma gözlenmedi (p>0.05).
Sonuç
Ramelteonun, sağlam kemik dokusu üzerinde yüksek
doz metotreksatın neden olduğu kemik toksisitesinde,
kemik döngüsünde, histopatolojik ve immünohistokimyasal
olarak anabolik bir işlevi olmadığı gösterilmiştir.

Keywords

Metotreksat, Ramelteon, Melatonin, Katepsin-K, RUNX2

Project Number

TSG-2020-8134

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