Does ramelteon have an ameliorative effect in MTX-induced testicular injury?

Abstract

Aims: The aim of this study was to investigate the potential protective effect of Ramelteon (RMT), which exhibits antioxidant, anti-inflammatory and antiapoptotic properties, against testicular damage induced by Methotrexate (MTX), which is widely used in the treatment of various diseases, including chemotherapy. Methods: 32 Wistar albino rats were equally divided into four groups: Control (group I), MTX (group II), MTX+RMT (group III) and RMT (group IV). Histologic evaluation was performed using Hematoxylin and Eosin (H&E) staining, immunohistochemical analysis using TNF-alpha and Cas-3, and biochemical evaluation using TAS, TOS and OSI. Results: Histologic analysis using H&E staining revealed a significant difference between group I and groups II and III (p<0.05), while no significant difference was observed between group IV and the other groups (p>0.05). While normal histologic structures were observed in groups I and IV, histopathologic findings were noted in groups II and III. Immunohistochemical evaluation of TNF-alpha and Cas-3 showed a significant difference between group I and groups II and III (p<0.05), while no significant difference was observed between group IV and other groups (p>0.05). The highest immunostaining intensity was observed in group II. Biochemical evaluation revealed statistically significant differences in TAS, TOS and OSI parameters reflecting oxidative stress differences between the groups (p<0.05). Conclusion: Anti-inflammatory, antioxidant and antiapoptotic properties of RMT demonstrated its protective effect against MTX-induced testicular injury in rats. Histological, immunohistochemical and biochemical analyses underline the potential role of RMT as a protective agent in MTX-induced testicular injury. This research aims to contribute to the understanding of potential applications to reduce the adverse effects of MTX therapy on reproductive health.

Keywords

• Methotrexate
• ramelteon
• rat
• testicular injury

References

1. Yulug E, Turedi S, Alver A, Turedi S, Kahraman C. Effects of resveratrol on methotrexate-induced testicular damage in rats. Sci World J. 2013;2013:1-6.
2. Belhan S, Çomaklı S, Küçükler S, Gülyüz F, Yıldırım S, Yener Z. Effect of chrysin on methotrexate-induced testicular damage in rats. Andrologia. 2019;51(1):1-9.
3. Özgöçmen M, Aşcı H, Doğan HK, İlhan İ, Pekgöz Ş, Mustafaoğlu A. A study on Wistar albino rats: investigating protective role of ramelteon on liver damage caused by methotrexate. Drug Chem Toxicol. 2022;45(6):2678-2685.
4. Pekgöz S, Asci H, Erzurumlu Y, et al. Nebivolol alleviates liver damage caused by methotrexate via AKT1/Hif1α/eNOS signaling. Drug Chem Toxicol. 2022;45(5):2153-2159.
5. Abdul-Hamid M, Abdel-Reheim ES, Hegazy W, et al. Impact of gervital against histopathological, ultrastructural, and biochemical alterations caused by methotrexate or azathioprine in albino rat testis. Environ Sci Pollut Res. 2023;30(8):21914-21926.
6. Sönmez MF, Çilenk KT, Karabulut D, et al. Protective effects of propolis on methotrexate-induced testis injury in rat. Biomed Pharmacother. 2016;79:44-51.
7. Wang Y, Zhao TT, Zhao HY, Wang H. Melatonin protects methotrexate-induced testicular injury in rats. Eur Rev Med Pharmacol Sci. 2018;22(21):7517-7525.
8. Delen O, Uz YH. Protective effect of pyrrolidine dithiocarbamate against methotrexate-induced testicular damage. Hum Exp Toxicol. 2021;40(12_suppl):S164-S177.

9. Borovskaya TG, Shchemerova YA, Bokhan EA, et al. Experimental evaluation of long-term toxic effects of methotrexate on male reproductive system. Bull Exp Biol Med. 2021;171(1):37-40.
10. Pınar N, Çakırca G, Özgür T, Kaplan M. The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother. 2018;97(August 2017):1486-1492.
11. Pınar N, Kaplan M, Özgür T, Özcan O. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother. 2018;102(December 2017):758-764.
12. Borja NL, Daniel KL. Ramelteon for the treatment of insomnia. Clin Ther. 2006;28(10):1540-1555.
13. Yang S, Wang J, Wang D, Guo L, Yu D. Melatonin receptor agonist ramelteon suppresses lps-ınduced neuroinflammation in astrocytes. ACS Chem Neurosci. 2021;12(9):1498-1505.
14. Mcgechan A, Wellington K. Ramelteon. 2005;19(12):1057-1065.
15. Wu GC, Peng CK, Liao WI, Pao HP, Huang KL, Chu SJ. Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production. Respir Res. 2020;21(1):1-17.
16. Asci H, Ozmen O, Ellidag HY, Aydin B, Bas E, Yilmaz N. The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal. 2017;25(4):890-897.
17. Wang J, Jiang C, Zhang K, 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(October 2018):345-355.
18. 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 J Urol. 2011;17(1):6-10.
19. Sukhorum W, Welbat JU, Krutsri S, Iamsaard S. Protective effect of melatonin against methotrexate-induced testicular damage in the rat model: an experimental study. Int J Reprod Biomed. 2020;18(5):327-338.
20. Omar N, El-Kot AA, Khalifa EI. Protective role of thyme leave extract on methotrexate-induced histological and immunohistochemical changes in testes of rats. Egypt J Hosp Med. 2021;83(1):1230-1238.