UTERUS DOKUSU ÜZERİNE DOKSORUBİSİN VE AGOMELATİN’İN ETKİLERİ: HİSTOPATOLOJİK BİR ÇALIŞMA

Öz

Amaç Antrasiklin bir antibiyotik olan doksorubisin (DOX) çeşitli kanser tiplerinin tedavilerinde kullanılan bir ilaçtır. Apoptozis, inflamasyon, serbest radikal oluşumu ve mitokondriyal DNA hasarı sonucunda akciğer, böbrek, kalp, karaciğer, beyin ve over gibi organlarda hasara neden olur. Agomelatin (AGO) güçlü bir antioksidan olan melatoninin agonistidir. AGO’nun; kalp, beyin, böbrek, karaciğer ve over dokularında anti-inflamatuar ve antioksidan etkinliği çeşitli çalışmalarla ortaya konulmuştur. Bu çalışmada, DOX’un uterus dokusunda neden olduğu toksisite üzerine AGO’nun koruyucu etkisini belirlemeyi amaçladık. Gereç ve Yöntem Bu çalışma her grupta 8 dişi sıçan olacak şekilde toplamda 32 sıçan üzerinde gerçekleştirildi. Deney grupları; Kontrol, DOX, DOX+AGO20 ve DOX+AGO40 şeklinde 4 gruptan oluşturuldu. Kontrol grubunda yer alan sıçanlara 12 gün boyunca günde tek doz 1 ml serum fizyolojik (SF) oral gavajla ve sadece 12. gün intraperitoneal olarak verildi. DOX grubundaki hayvanlara 12 gün boyunca her gün oral gavaj yöntemiyle 1 ml SF ve 12.günde intraperitoneal (i.p.) olarak tek doz 40 mg/kg DOX verildi. DOX+AGO20 grubundaki hayvanlara 12 gün boyunca her gün oral gavaj yöntemiyle 20 mg/kg AGO ve 12.gün i.p. olarak 40 mg/kg DOX verildi. DOX+AGO40 grubunda yer alan hayvanlara da 12 gün boyunca her gün oral gavaj tekniğiyle 40 mg/kg AGO ve 12.günde 40 mg/kg i.p. olarak DOX verildi. Bulgular Yapılan histopatolojik işlemler ve incelemeler sonucunda DOX grubuna ait uterus dokularında oluşan hasarlanmaya karşı, DOX+ AGO20 ve DOX+AGO40 kombine uygulanan gruplarda hasarın azaldığı görülmüştür. İmmün boyamalar (E-kadherin ve eNOS) sonucunda da DOX grubunda boyanma şiddetinin fazla, DOX+ AGO20 ve DOX+AGO40 kombine gruplarda ise daha az olduğu tespit edilmiştir. Sonuç Sonuç olarak DOX’un uterus dokusunda oluşturduğu hasara karşı AGO’nun koruyucu etkisi olduğunu düşünmekteyiz.

Anahtar Kelimeler

• Uterus
• Doksorubisin
• Agomelatin
• Histopatoloji

THE EFFECTS OF DOXORUBICIN AND AGOMELATIN ON UTERUS TISSUE: A HISTOPATHOLOGICAL STUDY

Öz

Objective Doxorubicin (DOX), an anthracycline antibiotic, is a drug used in the treatment of various types of cancer. It causes damage to organs such as lung, kidney, heart, liver, brain and ovary as a result of apoptosis, inflammation, free radical formation, mitochondrial DNA damage. Agomelatine (AGO) is an agonist of the powerful antioxidant melatonin. Anti-inflammatory and antioxidant activity of AGO in heart, brain, kidney, liver and ovary tissues has been demonstrated by various studies. In this study, we aimed to determine the protective effect of AGO on the toxicity of doxorubicin in the uterine tissue. Material and Method This study was carried out on 32 rats, 8 female rats in each group. Experimental groups: Control was formed from 4 groups as DOX, DOX+AGO20 and DOX+AGO40. The rats in the control group were given 1 ml of saline (SF) once a day by oral gavage for 12 days and intraperitoneally only on the 12th day. The animals in the DOX group were given 1 ml of saline by oral gavage every day for 12 days and a single dose of 40 mg/kg DOX intraperitoneally (i.p.) on the 12th day. Animals in the DOX+AGO20 group were given 20 mg/kg AGO by oral gavage method every day for 12 days. On the 12th day, i.p. 40 mg/kg DOX was given. Animals in the DOX+AGO40 group were given 40 mg/kg AGO by oral gavage method every day for 12 days. On the 12th day, i.p. 40 mg/kg DOX was given. Results As a result of the histopathological procedures and examinations, it was observed that the damage to the uterine tissues of the DOX group was reduced in the groups that were administered DOX+ AGO20 and DOX+AGO40 combined. As a result of immunostaining (E-cadherin and eNOS), it was determined that the staining intensity was higher in the DOX group and less in the DOX+ AGO20 and DOX+AGO40 combined groups. Conslusion As a result, we think that AGO has a protective effect against the damage caused by DOX in the uterine tissue.

Anahtar Kelimeler

• Uterus
• Doxorubicin
• Agomelatine
• Histopathology

Kaynakça

1. 1. Pugazhendhi A, Edison TNJI, Velmurugan BK, Jacob JA, Karuppusamy I. Toxicity of doxorubicin (Dox) to different experimental organ systems. Life sciences 2018; 200:26-30.
2. 2. Chabner BA, Amrein PC, Druker B, Michaelson MD, Mitsiades CS, Goss PE et al. Antineoplastic agents. The pharmacological basis of therapeutics 9/e. 2006:1315-465.
3. 3. Vendramini V, Sasso-Cerri E, Miraglia SM. Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status. Reproductive Biology and Endocrinology 2010; 8:1-3.
4. 4. Nishi K, Gunasekaran VP, Arunachalam J, Ganeshan M. Doxorubicin- induced female reproductive toxicity: an assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats. Drug and Chemical Toxicology 2017; 41(1): 72-8.
5. 5. Ashour AE, Sayed-Ahmed MM, Abd-Allah AR, Korashy HM, Maayah ZH, Alkhalidi H et al. Metformin rescues the myocardium from doxorubicin-induced ener starvation and mitochondrial damage in rats. Oxid Med Cell Longev 2012;2012:434195.
6. 6. De Leonardis V, Neri B, Bacalli S, Cinelli P. Reduction of cardiac toxicity of anthracyclines by l-carnitine: preliminary overview of clinical data. Int J Clin Pharmacol Res 1985;5(2):137-42.
7. 7. Morishima I, Matsui H, Mukawa H, Hayashi K, Toki Y, Okumura K et al. Melatonin, a pineal hormone with antioxidant property, protects against adriamycin cardiomyopathy in rats. Life Sci 1998;63(7):511–21.
8. 8. Tatlidede E, Sehirli O, Velioglu-Ogunc A, Çetinel Ş, Yeğen BÇ, Yarat A et al. Resveratrol treatment protects against doxorubicin- induced cardiotoxicity by alleviating oxidative damage. Free Radic Res 2009;43(3):195-205.

9. 9. Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 2001;61(2):771-7.
10. 10. Ikeda Y, Aih AK, Akaike M, Sato T, Ishikawa K, Ise T et al. Androgen receptor conteracts doxorubicin-induced cardiotoxicity in male mice. Mol Endocrinol 2010;24(7):1338-48.
11. 11. Ascensao A, Lumini-Oliveira J, Machado NG, Ferreira RM, Gonçalves IO, Moreira AC et al. Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opning in doxorubicin-treated rats. Clin Sci (Lond) 2011;120(1):37-49.
12. 12. Montaigne D, Marechal X, Preau S, Baccouch R, Modine T, Fayad G et al. Doxorubicin induces mitochondrial permeability transition and contractile dysfunction in the human myocardium. Mitochondrion 2011;11(1):22-6.
13. 13. Kalivendi SV, Konorev EA, Cunningham S, Vanamala SK, Kaji EH, Joseph J et al. Doxorubicin activates nuclear factor of activated t-lymphocytes and fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J 2005;389(2):527-39.
14. 14. Jang Ym, Kendaiah S, Drew B, Phillips T, Selman C, Julian D et al. Doxorubicin treatment ın vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett 2004;577(3):483-90.
15. 15. Wang S, Kotamraju S, Konorev E, Kalivendi S, Joseph J, Kalyanaraman B. Activation of nuclear factor Kappa B duringdoxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem J 2002;367(3):729-40.
16. 16. Aygun H, Gul SS. Bir sıçan modelinde melatonin ve agomelatinin doksorubisin kaynaklı kardiyotoksisite üzerindeki kardiyoprotektif etkisi: elektrokardiyografik, sintigrafik ve biyokimyasal bir çalışma. Bratislavske lekarske listy 2019;120(4):249-55.
17. 17. Kennedy SH, Rizvi S, Fulton K, Rasmussen J. A Double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. Journal of Clinical Psychopharmacology 2008;28(3):329-33.
18. 18. Demirdaş A, Nazıroğlu M, Ünal GÖ. Agomelatine reduces brain, kidney and liver oxidative stress but increases plasma cytokine production in the rats with chronic mild stress-induced depression. Metabolic brain disease 2016;31(6):1445-453.
19. 19. Başol N, Erbaş O, Çavuşoğlu T, Meral A, Ateş U. Beneficial effects of agomelatine in experimental model of sepsis-related acute kidney injury. Ulus Travma Acil Cerrahi Derg 2016; 22(2):121-6.
20. 20. Song Y, Chan CW, Brown GM, Pang SF, Silverman M. Studies of the renal action of melatonin: evidence that the effects are mediated by 37 kda receptors of the mel1a subtype localized primarily to the basolateral membrane of the proximal tubule. FASEB J 1997;11(1): 93-100.
21. 21. Montgomery MD, Chan T, Swigart PM, Myagmar BE, Dash R, Simpson PC. An Alpha-1A adrenergic receptor agonist prevents acute doxorubicin cardiomyopathy in male mice. Plos One 2017;12(1): E0168409.
22. 22. He J, Fang P, Zheng X, Wang C, Liu T, Zhang B et al. Inhibitory effect of celecoxib on agomelatine metabolism in vitro and in vivo. Drug Des Devel Ther 2018;9(12):513-19.
23. 23. Molteni R, Macchi F, Zecchillo C, Dell'agli M, Colombo E, Calabrese F et al. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur Neuropsychopharmacol 2013;23(11):1645-55.
24. 24. Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimen in cases of urinary bladder carcinoma. African Journal of Urology 2011;17(1):6-10.
25. 25. Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther 2014;10(4):853-8.
26. 26. Demirbağ HO. Doksorubisin kaynaklı ovaryum hasarında adipoz kökenli mezenkimal kök hücrelerin PTEN/AKT/FOXO3A yolağı ve folikülogenez üzerine etkilerinin incelenmesi. Mersin Üniversitesi Sağlık Bilimleri Enstitüsü Histoloji ve Embriyoloji Anabilim Dalı Doktora Tezi. Mersin: Mersin Üniversitesi. 2020.
27. 27. Roness H, Kashi O, Meirow D. Prevention of chemotherapy-induced ovarian damage. Fertil Steril 2016;105(1):20-9.
28. 28. Zhang T, He WH, Feng LL, Huang HG. Effect of doxorubicin-induced ovarian toxicity on mouse ovarian granulosa cells. Regul toxicol pharmacol 2017;86:1-10.
29. 29. Khalaf HM, Abdalla AM, Ahmed AF, Abdel-Aziz A M. Role of nitric oxide in mediating the cardioprotective effect of agomelatine against isoproterenol-induced myocardial injury in rats. Naunyn Schmiedebergs Arch Pharmacol 2020;393(10):1809-23.
30. 30. Jia P, Liu C, Wu N, Jia D, Sun Y. Agomelatine protects against myocardial ischemia reperfusion injury by inhibiting mitochondrial permeability transition pore opening. American journal of translational research 2018;10(5):1310-323.
31. 31. Ercan Z, Kaçar E, Serhatlıoğlu I. Bir antidepresan olan agomelatinin sıçan miyometriyum kontraksiyonları üzerine etkilerinin incelenmesi. Fırat Üniversitesi Sağlık Bilimleri Tıp Dergisi 2017;31(2): 89-2.
32. 32. Mohan UP, Pb TP, Kunjiappan S, Arunachalam S. A hypothesis concerning the role of PPAR family on cardiac energetics in Adriamycin-induced cardiomyopathy. J Appl Toxicol 2022;42(12):1910-20.
33. 33. Abdella EM, Ahmed R. Suppression of doxorubicin apoptotic, histopathologic, mutagenic and oxidative stress effects in male mice bone marrow and testis tissues by aqueous rosemary leaves extract. IJCP 2009;2(1):35-49.
34. 34. Gewirtz DA. Emerging concepts: New article category in molecular pharmacology. Mol Pharmacol 2020;98(4):350.
35. 35. Samare-Najaf M, Zal F, Safari S, Koohpeyma F, Jamali N. Stereological and histopathological evaluation of doxorubicin- induced toxicity in female rats' ovary and uterus and palliative effects of quercetin and vitamin E. Hum Exp Toxicol 2020;39(12):1710-24.
36. 36. Fabbri R, Macciocca M, Vicenti R, Caprara G, Piccinni MP, Paradisi R. Epigallocatechin-3-gallate inhibits doxorubicin-induced inflammation on human ovarian tissue. Biosci Rep 2019;39(5): BSR20181424.
37. 37. Cengiz Ö. Doxorubicin ile oluşturulan ovaryum toksisitesi üzerine farklı doz selenyumun etkilerinin değerlendirilmesi. Erciyes Üniversitesi, Sağlık Bilimleri Enstitüsü Histoloji ve Embriyoloji Anabilim Dalı,Yüksek Lisans Tezi. Kayseri: Erciyes Üniversitesi. 2019.