ÖZET

Amaç:

Otoimmün hastalıklar ve kanserlerin tedavisinde kullanılan bir ilaç olan metotreksat (MTX), bir folik asit antagonistidir ancak gastrointestinal sistem (GİS) üzerinde toksik etkileri vardır. Bu çalışmada, bir melatonin reseptör agonisti olan Ramelteon’un (RAM) sıçanların barsak dokusunda MTX ile indüklenen toksisite üzerindeki anti-enflamatuvar, antioksidan ve anti-apoptotik etkilerini araştırdık.

Yöntemler:

Otuz iki erkek Wistar albino rat rastgele 4 gruba ayrıldı: Kontrol grubu, MTX grubu, MTX + RAM grubu ve RAM grubu. Yedi gün boyunca tek doz 0,1 mL 20 mg/kg MTX, salin veya 0,1 mL 10 mg/kg RAM oral yoldan uygulandı. Hayvanlar, son ilaç uygulamasından sonra, yani 7. günün sonunda sakrifiye edildi. Daha sonra, barsak dokuları biyokimyasal, histopatolojik ve immünohistokimyasal analizler için toplandı.

Bulgular:

Kontrol ve RAM gruplarında normal histolojik bulgular ve biyokimyasal parametreler gözlemlenirken, MTX grubunda mononükleer hücre infiltrasyonları, hemorajik alanlar, submukozada dejenerasyonlar ve barsak kesitlerinde Lieberkuhn kriptleri gözlendi. MTX grubunda kaspaz-3 (Cas-3) ve tümör nekroz faktör-alfa (TNF-α) ekspresyonları, total oksidan seviyesi (TOS) ve oksidatif stres indeksi (OSI) arttı ve total antioksidan seviyesi (TAS) azaldı. RAM tedavisi Cas-3 ve TNF-α düzeylerini, TOS, OSI seviyelerini azaltırken TAS seviyelerini arttırdı.

Sonuç:

Bu çalışmanın sonucunda RAM, barsak dokusunda MTX kaynaklı toksisite üzerinde anti-apoptotik, antioksidan ve anti-enflamatuvar etkiler gösterdi. Bu nedenle, GİS üzerindeki yan etkileri hafifletmek için MTX benzeri toksisitelerde RAM’nin kullanılabileceği öne sürülmüştür.

References

Cronstein BN, Bertino JR. Methotrexate. Birkhäuser; 2012.

Editore S. Methotrexate in the treatment of rheumatic diseases. SICS Editore; 2014.

Jones V. Methotrexate: The Fast Action Drug Used to Treat Rheumatoid Arthritis, Severe Psoriasis and Breast Cancer. Independently Published; 2019.

Neradil J, Pavlasova G, Veselska R. New mechanisms for an old drug; DHFR- and non-DHFR-mediated effects of methotrexate in cancer cells. Klin Onkol 2012;25 (Suppl 2):2S87-92.

Freyer CW, Gier S, Moyer ME, et al. Leucovorin Rescue After Methotrexate Graft-Versus-Host Disease Prophylaxis Shortens the Duration of Mucositis, Time to Neutrophil Engraftment, and Hospital Length of Stay. Transplant Cell Ther 2021;27:431.e1-e431.e8.

Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, et al. Methotrexate an Old Drug with New Tricks. Int J Mol Sci 2019;20:5023.

Zeeshan HM, Lee GH, Kim HR, Chae HJ. Endoplasmic Reticulum Stress and Associated ROS. Int J Mol Sci 2016;17:327.

Baer PC, Koch B, Geiger H. Kidney Inflammation, Injury and Regeneration. Int J Mol Sci 2020;21:1164.

Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014;20:1126-67.

Cristiana F, Elena A. Reactive Oxygen Species (ROS) in Living Cells. BoD - Books on Demand; 2018.

Wang Q, Lu Q, Guo Q, Teng M, Gong Q, Li X, et al. Structural basis of the ligand binding and signaling mechanism of melatonin receptors. Nat Commun 2022;13:454.

Oishi A, Gbahou F, Jockers R. Melatonin receptors, brain functions, and therapies. Handb Clin Neurol 2021;179:345-56.

Yang S, Wang J, Wang D, Guo L, Yu D. Melatonin Receptor Agonist Ramelteon Suppresses LPS-Induced Neuroinflammation in Astrocytes. ACS Chem Neurosci 2021;12:1498-505.

Gu C, Wang F, Zhang YT, Wei SZ, Liu JY, Sun HY, et al. Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming. Aging Cell 2021;20:e13375.

Kandezi N, Majdi F, Davoudizadeh R, Motaghinejad M, Safari S. Preventive Properties of Ramelteon against Cocaine-Induced Autophagia and Apoptosis: A Hypothetic Role of TNF-a Receptor Involvement and JNK/Bcl-2-Beclin1 or Bcl-2/Bax Signaling Pathway. Int J Prev Med 2020;11:36.

Asvadi I, Hajipour B, Asvadi A, Asl NA, Roshangar L, Khodadadi A. Protective effect of pentoxyfilline in renal toxicity after methotrexate administration. Eur Rev Med Pharmacol Sci 2011;15:1003-9.

Wang J, Jiang C, Zhang K, Lan X, Chen X, Zang W, et al. Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway. Free Radic Biol Med 2019;131:345-55.

Refaiy A, Muhammad E, ElGanainy EO. 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;6-10.

Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277-85.

Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103-11.

Nayak RR, Alexander M, Deshpande I, Stapleton-Gray K, Rimal B, Patterson AD, et al. Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation. Cell Host Microbe 2021;29:362-77.e11.

Kuiken NSS, Rings EHHM, Tissing WJE. Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients. Crit Rev Oncol Hematol 2015;94:87-97.

Nagakubo J, Tomimatsu T, Kitajima M, Takayama H, Aimi N, Horie T. Characteristics of transport of fluoresceinated methotrexate in rat small intestine. Life Sci 2001;69:739-47.

Haustein U-F, Rytter M. Methotrexate in psoriasis: 26 years’ experience with low-dose long-term treatment . J Eur Acad Dermatol Venereol 2000;14:382-8.

Borovskaya TG, Shchemerova YA, Bokhan EA, Grigor’eva VA, Vychuzhanina AV, Poluektova ME, et al. Experimental Evaluation of Long-Term Toxic Effects of Methotrexate on Male Reproductive System. Bull Exp Biol Med 2021;171:37-40.

Keefe DMK. Gastrointestinal mucositis: a new biological model. Support Care Cancer 2004;12:6-9.

Morsy M, El-Sheikh A, Hamouda A. Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats. Pharmacogn Mag 2016;12(Suppl 1):S76-81.

Tomás-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 2005;39:99-104.

Wang T, Li Z, Xia S, et al. The Protective Effects of Ramelteon Against Isoflurane-Induced Insults and Inflammatory Response in Brain Microvascular Endothelial Cells. Neurotox Res 2021;39:67-86.

Ramelteon, Anti-apoptotik, Anti-enflamatuvar ve Antioksidan Özellikler Göstererek Barsak Dokusunu Metotreksatın Neden Olduğu Hasara Karşı Korur

ÖZET

References