Pathologic Examination of the Protective Effect of Glycyrrhizin on Cyclophosphamide-induced Hemorrhagic Cystitis in Rats

Year 2019, , 89 - 96, 31.03.2019

Okan Erdogan Hikmet Keles

https://doi.org/10.30607/kvj.515979

Cited By: 2

Abstract

Cyclophosphamide (CP) is a
widely used anti-neoplastic agent in humans and small animals and also has some
adverse effects in them. The most common adverse effect of CP is hemorrhagic
cystitis (HS). The use of Mesna may prevent HS, but is insufficient for some
side effects. In this study, the effect of glycyrrhizin (GLY), which is one of the active substances of licorice
root, was examined against CP-related
side effects. The experiment was designed with 49 male Sprague Dawley
rats. The Control group received only physiological saline and the CP group
only CP. CP+Mesna group received CP and also three dose of Mesna. The animals
in the CP+GLY100 and CP+GLY200 groups were received three doses of GLY, 100
mg/kg and 200 mg/kg dose, respectively. The previous protocol was applied to
the CP+Mesna+GLY100 and CP+Mesna+GLY200 groups and only the first GLY
application was replaced with Mesna. In this study, it was recorded that
bladder macroscopy and histopathology were better preserved in GLY applicated
groups compared to CP group. However, it was observed that this protection was
slightly weaker than the Mesna and GLY-Mesna combinations. From this point of
view, it was observed that GLY could be preventive in CP-related HS, in
addition it could also support to Mesna applications.

Keywords

Cyclophosphamide, Glycyrrhizin, Hemorrhagic cystitis, Mesna, Pathology

Ratlarda Siklofosfamid ile İndüklenen Hemorajik Sistitisde Glycyrrhizinin Koruyucu Etkilerinin Patolojik Olarak İncelenmesi

Abstract

Siklofosfamid (CP) yaygın olarak kullanılan bir
anti-neoplastik ajandır ve bazı yan etkilere sahiptir. Siklofosfamidin en
belirgin yan etkisi hemorajik sistitistir (HS). Mesna kullanımı HS’yi
önleyebilmekte ancak diğer bazı yan etkiler için yetersiz kalmaktadır. Bu
çalışmada, CP ilişkili HS’ye karşı, meyan kökünün aktif içeriklerinden olan
glycyrrhizinin (GLY) etkisi incelenmiştir. Çalışma, 49 adet, erkek Sprague
Dawley rat ile dizayn edilmiştir. Kontrol grubuna sadece fizyolojik tuzlu su,
CP grubuna ise sadece CP verilmiştir. CP+Mesna grubuna CP ve ayrıca 3 doz Mesna
uygulanmıştır. CP+GLY100 ve CP+GLY200 gruplarına; CP ve sırasıyla 100 mg/kg ile
200 mg/kg olmak üzere üç doz GLY uygulanmıştır. Bir önceki protokol
CP+Mesna+GLY100 ve CP+Mesna+GLY200 gruplarınada uygulanmış olup sadece ilk GLY
uygulaması Mesna ile değiştirilmiştir. Çalışmada GLY uygulanan gruplarda CP
grubuna kıyasla mesane makroskobisi ve histopatolojisinin daha iyi bir şekilde
korunmuş olduğu kaydedilmiştir. Ancak, bu korumanın Mesna ve GLY-Mesna
kombinasyonlarına kıyasla biraz daha zayıf kaldığı izlenmiştir. Buradan yola
çıkılarak GLY’in CP ilişkili HS’de önleyici olabileceği aynı zamanda Mesna
uygulamalarına destek verebileceği kanaatine varılmıştır.

Keywords

Glycyrrhizin, Hemorajik sistitis, Mesna, Patoloji, Siklofosfamid

References

• Akan H, Balos M. GAP Bölgesi’nden toplanan meyan kökü (Glycrrhiza glabra L.) taksonunun ihracat durumu, etnobotanik özellikleri ve tıbbi önemi. Fırat Üniversitesi Fen ve Mühendis Bilim Derg. 2008; 20(2):233–241. in Turkish
• Arafa HMM. Uroprotective effects of curcumin in cyclophosphamide-induced haemorrhagic cystitis paradigm. Basic Clin Pharmacol Toxicol. 2009; 104(5):393–399.
• Asımgil A. Şifalı Bitkiler. İstanbul: Timaş Yayınları; 1997. in Turkish.
• Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008; 22(6):709–724.
• Assafim M, Ferreira MS, Frattani FS, Guimarães JA, Monteiro RQ, Zingali RB. Counteracting effect of glycyrrhizin on the hemostatic abnormalities induced by Bothrops jararaca snake venom. Br J Pharmacol. 2006; 148(6):807–813.
• Ballen KK, Becker P, Levebvre K, Emmons R, Lee K, Levy W, Stewart FM, Quesenberry P, Lowry P. Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients. Oncology. 1999; 57(4):287–292.
• Baytop T. Türkçe Bitki Adları Sözlüğü. Ankara: Türk Dil Kurumu Yayınları; 1999a. in Turkish.
• Baytop T. Türkiye’de Bitkiler ile Tedavi Geçmişte ve Bugün. 2. baskı. Nobel Tıp Kitapevleri; 1999b. in Turkish.
• Boeira VT, Leite CE, Santos AA, Edelweiss MI, Calixto JB, Campos MM, Morrone FB. Effects of the hydroalcoholic extract of Phyllanthus niruri and its isolated compounds on cyclophosphamide-induced hemorrhagic cystitis in mouse. Naunyn Schmiedebergs Arch Pharmacol. 2011; 384(3):265-275.
• Çınar İ. Effect of temperature and time on licorice root (Glycyrrhiza glabra L.) extraction and modelling extraction kinetics. Electron J Food Technol. 2012; 7(2):21–30. in Turkish with English abstract.
• Del Pizzo JJ, Chew BH, Jacobs SC, Sklar GN. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen: long-term followup. J Urol. 1998; 160(3 Pt 1):731–733. deVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urol. 1990; 143(1):1–9.
• Dorris K, Fouladi M, Davies SM, Perentesis JP, Lawrence JM, Chow LML, Assa’ad A, Uygungil B, Jodele S. Severe allergic reactions to thiol-based cytoprotective agents mesna and amifostine in a child with a supratentorial primitive neuroectodermal tumor. J Pediatr Hematol Oncol. 2011; 33(6):e250-e252.
• Francischetti IM, Monteiro RQ, Guimarães JA, Francischetti B. Identification of glycyrrhizin as a thrombin inhibitor. Biochem Biophys Res Commun. 1997; 235(1):259–263.
• Goker H, Haznedaroglu I, Ercetin S, Kirazli S, Akman U, Ozturk Y, Firat H. Haemostatic Actions of the Folkloric Medicinal Plant Extract Ankaferd Blood Stopper®. J Int Med Res. 2008; 36(1):163–170.
• Gressier B, Lebegue N, Brunet C, Luyckx M, Dine T, Cazin M, Cazin JC. Scavenging of reactive oxygen species by letosteine, a molecule with two blocked-SH groups. Comparison with free-SH drugs. Pharm World Sci. 1995; 17(3):76–80.
• Hamsa TP, Kuttan G. Protective role of Ipomoea obscura (L.) on cyclophosphamide-induced uro- and nephrotoxicities by modulating antioxidant status and pro-inflammatory cytokine levels. Inflammopharmacology. 2011; 19(3):155–167.
• Leong C, Sun H, Wang Q, Ma J. Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model. J Clin Neurosci. 2018; 47:278–284.
• Ito M, Sato A, Hirabayashi K, Tanabe F, Shigeta S, Baba M, De Clercq E, Nakashima H, Yamamoto N. Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV). Antiviral Res. 1988; 10(6):289–298.
• Kankaya A. Pathologic examination of the protective effects of ellagic acid on cyclophosphamide-induced hemorrhagic cystitis in rats. MSc thesis. Afyon Kocatepe University Health Science Institute, Afyonkarahisar, 2017. in Turkish with English abstract.
• Keles H, Bozkurt MF, Ulucan A, Demirel HH, Yuksel H, Karadas E, Ozkul IA. The role of inducible nitric oxide synthase in urinary bladders of cattle with enzootic hematuria and its struggle with uroplakin III. Ank Üniversitesi Vet Fakültesi Derg. 2018; 65(4):341–348.
• Keles I, Bozkurt MF, Cemek M, Karalar M, Hazini A, Alpdagtas S, Keles H, Yildiz T, Ceylan C, Buyukokuroglu ME. Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna. Int Urol Nephrol. 2014; 46(12):2301–2310.
• Khaw SL, Downie PA, Waters KD, Ashley DM, Heath JA. Adverse hypersensitivity reactions to mesna as adjunctive therapy for cyclophosphamide. Pediatr Blood Cancer. 2007; 49(3):341–343.
• Kilic O, Akand M, Karabagli P, Piskin MM. Hemostatic Efficacy and Histopathological Effects of Ankaferd Blood Stopper in an Experimental Rat Model of Cyclophosphamide-induced Hemorrhagic Cystitis. Urology. 2016; 94:313.e7-313.e13.
• Kim S-H, Lee I-C, Lim J-H, Moon C, Bae C-S, Kim S-H, Shin D-H, Park S-C, Kim H-C, Kim J-C. Protective effects of pine bark extract on developmental toxicity of cyclophosphamide in rats. Food Chem Toxicol. 2012; 50(2):109–115.
• Lin CY, Keefe M. Mesna-induced photodistributed dermatosis. Clin Exp Dermatol. 2012; 37(4):358–360.
• Lin G, Nnane IP, Cheng TY. The effects of pretreatment with glycyrrhizin and glycyrrhetinic acid on the retrorsine-induced hepatotoxicity in rats. Toxicon. 1999; 37(9):1259–1270.
• Manikandan R, Kumar S, Dorairajan LN. Hemorrhagic cystitis: A challenge to the urologist. Indian J Urol. 2010; 26(2):159–166.
• Ohnishi M, Katsuki H, Fukutomi C, Takahashi M, Motomura M, Fukunaga M, Matsuoka Y, Isohama Y, Izumi Y, Kume T, Inoue A, Akaike A. HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacology. 2011; 61(5–6):975–980.
• Oter S, Korkmaz A, Oztas E, Yildirim I, Topal T, Bilgic H. Inducible nitric oxide synthase inhibition in cyclophosphamide induced hemorrhagic cystitis in rats. Urol Res. 2004; 32(3):185–189.
• Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung KE, Tsoukas MA, Geladari EV, Huh JY, Dincer F, Davis CR, Crowell JA, Mantzoros CS. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab. 2013; 98(12):4899–4907.
• Philips FS, Sternberg SS, Cronin AP, Vidal PM. Cyclophosphamide and urinary bladder toxicity. Cancer Res. 1961; 21:1577–1589.
• Ram A, Mabalirajan U, Das M, Bhattacharya I, Dinda AK, Gangal SV, Ghosh B. Glycyrrhizin alleviates experimental allergic asthma in mice. Int Immunopharmacol. 2006; 6(9):1468–1477.
• Rao BN, Anderson MB, Musser JH, Gilbert JH, Schaefer ME, Foxall C, Brandley BK. Sialyl Lewis X mimics derived from a pharmacophore search are selectin inhibitors with anti-inflammatory activity. J Biol Chem. 1994; 269(31):19663–19666.
• Santos AA, Leal PC, Edelweiss MIA, Lopes TG, Calixto JB, Morrone FB, Campos MM. Effects of the compounds MV8608 and MV8612 obtained from Mandevilla velutina in the model of hemorrhagic cystitis induced by cyclophosphamide in rats. Naunyn Schmiedebergs Arch Pharmacol. 2010; 382(5–6):399–407.
• Shiota G, Harada K, Ishida M, Tomie Y, Okubo M, Katayama S, Ito H, Kawasaki H. Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice. Carcinogenesis. 1999; 20(1):59–63.
• Sohn E-J, Kang D-G, Lee H-S. Protective effects of glycyrrhizin on gentamicin-induced acute renal failure in rats. Pharmacol Toxicol. 2003; 93(3):116–122.
• Soysal T. Hemorrhagic cystitis. Blood and Bone Marrow Transplantation Course, Turkish Hematology Society. 2004. in Turkish.
• Uto T, Morinaga O, Tanaka H, Shoyama Y. Analysis of the synergistic effect of glycyrrhizin and other constituents in licorice extract on lipopolysaccharide-induced nitric oxide production using knock-out extract. Biochem Biophys Res Commun. 2012; 417(1):473–478.
• Uygun S. The licorice as the favorite plant of the westerners and the imperialist rivalry. OTAM. 2015; 37/Bahar:337–373. in Turkish with English abstract.
• Vieira MM, Macêdo FYB, Filho JNB, Costa ACLV, Cunha AN, Silveira ER, Brito GAC, Ribeiro RA. Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats. Phytother Res. 2004; 18(2):135–141.
• Wang C-Y, Kao T-C, Lo W-H, Yen G-C. Glycyrrhizic acid and 18β-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-κB through PI3K p110δ and p110γ inhibitions. J Agric Food Chem. 2011; 59(14):7726–7733.
• West NJ. Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy. 1997; 17(4):696–706.
• Xu X, Malavé A. Protective effect of berberine on cyclophosphamide-induced haemorrhagic cystitis in rats. Pharmacol Toxicol. 2001; 88(5):232–237.