Araştırma Makalesi
BibTex RIS Kaynak Göster

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

Yıl 2022, Cilt: 29 Sayı: 1, 53 - 58, 01.03.2022
https://doi.org/10.17343/sdutfd.979473

Öz

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.

Destekleyen Kurum

SDU BAP

Proje Numarası

TSG-2020-8134

Teşekkür

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

Kaynakça

  • 1. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-77.
  • 2. Nilsson OS, Bauer FC, Brostrom LA, Nilsonne U. Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats. Cancer Res. 1984;44(4):1653-6.
  • 3. Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R. Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am. 1984;66(4):602-7.
  • 4. Demirel A, Kırnap M. Romatoid Artrit Tedavisinde Geleneksel Ve Güncel Yaklaşımlar. Sağlık Bilimleri Dergisi. 2010;19(1):74-84.
  • 5. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci. 2000;7(6):444-58.
  • 6. Chen J, Zhang L, Li C, Chen R, Liu C, Chen M. Lipophilized Epigallocatechin Gallate Derivative Exerts Anti-Proliferation Efficacy through Induction of Cell Cycle Arrest and Apoptosis on DU145 Human Prostate Cancer Cells. Nutrients. 2019;12(1).
  • 7. Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64(3).
  • 8. Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res. 2015;59(2):221-9.
  • 9. Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012;52(4):414-26.
  • 10. McGechan A, Wellington K. Ramelteon. CNS Drugs. 2005;19(12):1057-65; discussion 66-7.
  • 11. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021782s011lbl.pdf.
  • 12. Komori T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 2010;339(1):189-95.
  • 13. Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem. 2011;112(3):750-5.
  • 14. Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem. 1996;271(21):12517-24.
  • 15. Zaidi M, Troen B, Moonga BS, Abe E. Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res. 2001;16(10):1747-9.
  • 16. A. Refaiy EM, E. ElGanainy. 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):6-10.
  • 17. Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.
  • 18. Romao VC, Lima A, Bernardes M, Canhao H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res. 2014;60(2-3):289-310.
  • 19. Howard SC, McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. . Preventing and Managing Toxicities of High-Dose Methotrexate. The oncologist. 2016;21(12):1471-82.
  • 20. Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab. 1998;83(9):3121-9.
  • 21. Wheeler DL, Vander Griend RA, Wronski TJ, Miller GJ, Keith EE, Graves JE. The short- and long-term effects of methotrexate on the rat skeleton. Bone. 1995;16(2):215-21.
  • 22. Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274(31):22041-7.
  • 23. Halici M, Oner M, Guney A, Canoz O, Narin F, Halici C. Melatonin promotes fracture healing in the rat model. Eklem Hastalik Cerrahisi. 2010;21(3):172-7.
  • 24. Kose D, Kose A, Halici Z, Gurbuz MA, Aydin A, Ugan RA, et al. Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture. Eur J Pharmacol. 2020;887:173577.

MELATONİN AGONİSTİ OLAN RAMELTEONUN METOTREKSAT KAYNAKLI KEMİK TOKSİSİTESİNE KARŞI KORUYUCU ETKİSİ

Yıl 2022, Cilt: 29 Sayı: 1, 53 - 58, 01.03.2022
https://doi.org/10.17343/sdutfd.979473

Öz

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.

Proje Numarası

TSG-2020-8134

Kaynakça

  • 1. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-77.
  • 2. Nilsson OS, Bauer FC, Brostrom LA, Nilsonne U. Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats. Cancer Res. 1984;44(4):1653-6.
  • 3. Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R. Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am. 1984;66(4):602-7.
  • 4. Demirel A, Kırnap M. Romatoid Artrit Tedavisinde Geleneksel Ve Güncel Yaklaşımlar. Sağlık Bilimleri Dergisi. 2010;19(1):74-84.
  • 5. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci. 2000;7(6):444-58.
  • 6. Chen J, Zhang L, Li C, Chen R, Liu C, Chen M. Lipophilized Epigallocatechin Gallate Derivative Exerts Anti-Proliferation Efficacy through Induction of Cell Cycle Arrest and Apoptosis on DU145 Human Prostate Cancer Cells. Nutrients. 2019;12(1).
  • 7. Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64(3).
  • 8. Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res. 2015;59(2):221-9.
  • 9. Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012;52(4):414-26.
  • 10. McGechan A, Wellington K. Ramelteon. CNS Drugs. 2005;19(12):1057-65; discussion 66-7.
  • 11. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021782s011lbl.pdf.
  • 12. Komori T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 2010;339(1):189-95.
  • 13. Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem. 2011;112(3):750-5.
  • 14. Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem. 1996;271(21):12517-24.
  • 15. Zaidi M, Troen B, Moonga BS, Abe E. Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res. 2001;16(10):1747-9.
  • 16. A. Refaiy EM, E. ElGanainy. 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):6-10.
  • 17. Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.
  • 18. Romao VC, Lima A, Bernardes M, Canhao H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res. 2014;60(2-3):289-310.
  • 19. Howard SC, McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. . Preventing and Managing Toxicities of High-Dose Methotrexate. The oncologist. 2016;21(12):1471-82.
  • 20. Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab. 1998;83(9):3121-9.
  • 21. Wheeler DL, Vander Griend RA, Wronski TJ, Miller GJ, Keith EE, Graves JE. The short- and long-term effects of methotrexate on the rat skeleton. Bone. 1995;16(2):215-21.
  • 22. Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274(31):22041-7.
  • 23. Halici M, Oner M, Guney A, Canoz O, Narin F, Halici C. Melatonin promotes fracture healing in the rat model. Eklem Hastalik Cerrahisi. 2010;21(3):172-7.
  • 24. Kose D, Kose A, Halici Z, Gurbuz MA, Aydin A, Ugan RA, et al. Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture. Eur J Pharmacol. 2020;887:173577.
Toplam 24 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Klinik Tıp Bilimleri
Bölüm Araştırma Makaleleri
Yazarlar

Recep Dinçer 0000-0001-9088-3940

Tuba Baykal 0000-0003-4600-2207

Duygu Kumbul Doğuç 0000-0002-3879-9917

Emine Sarman 0000-0002-4671-9315

Devran Ceylan Bu kişi benim 0000-0002-7437-4465

Proje Numarası TSG-2020-8134
Yayımlanma Tarihi 1 Mart 2022
Gönderilme Tarihi 6 Ağustos 2021
Kabul Tarihi 6 Eylül 2021
Yayımlandığı Sayı Yıl 2022 Cilt: 29 Sayı: 1

Kaynak Göster

Vancouver Dinçer R, Baykal T, Kumbul Doğuç D, Sarman E, Ceylan D. PROTECTIVE EFFECT OF THE RAMELTEON, A MELATONIN AGONIST, AGAINST METHOTREXATE-INDUCED BONE-TOXICITY. SDÜ Tıp Fak Derg. 2022;29(1):53-8.

                                                                                         14791


Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi/Medical Journal of Süleyman Demirel University is licensed under Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International.