Dilan ÇETİNAVCI, Engin YENİLMEZ, Ayşe Firuze BIYIK, Ahmet ALVER, Neslihan SAĞLAM

Rosmarinik asidin sıçanlarda siklofosfamid ile indüklenen nefrotoksisite üzerine etkileri

Amaç: Siklofosfamid (CP) antineoplastik bir ajandır. Birçok kanser türünün tedavisinde kullanılmaktadır. Rosmarinik asit (RA), antiinflamatuar, antitümör, antibakteriyel ve antimikrobiyal etkiler gibi dikkate değer biyolojik aktiviteler sergiler. Bu çalışmanın amacı, rosmarinik asidin CP kaynaklı nefrotoksisiteye etkisini değerlendirmektir. Gereç ve Yöntem: On sekiz erkek Sprague Dawley sıçanı rastgele 3 eşit gruba ayrıldı. Sham grubuna (n=6): %0,9 salin solüsyonu/8 gün boyunca/oral + %0,9 salin solüsyonu/8. gün/intraperitoneal; CP grubuna (n=6): %0,9 salin solüsyonu/8 gün boyunca/oral + 200 mg/kg/8. gün/intraperitoneal CP; CP+RA grubu (n=6): 100 mg/kg/8 gün boyunca/oral RA + 200 mg/kg/8. gün/intraperitoneal CP uygulandı. Toplanan dokularda Hematoksilen ve Eozin, Periyodik Asit-Schiff ve Masson Trikrom boyamaları yapıldı. Bulgular: Histopatolojik değerlendirmede CP grubunda tübüler atrofi, glomerüler hasar, vasküler konjesyon, vakuolizasyon ve interstisyel inflamasyon saptandı. Histopatolojik skorlar CP+RA grubunda CP grubuna göre anlamlı derecede düşüktü. Sham grubu ile karşılaştırıldığında CP grubunda intertübüler fibrozis gözlendi. Rosmarinik asit ile fibrozis azaldı. PAS ile CP grubu kesitlerinde, tübüler epitel vakuolizasyonu, fırçamsı kenar ve bazal membran bozulması gözlendi. Bu sonuçlar rosmarinik asit ile azaldı. CP grubunda artan kan üre nitrojen değeri (BUN) CP+RA grubunda daha düşükken, CP grubunda azalan SOD değeri CP+RA grubunda daha yüksekti. Sonuç: RA' nın böbrekte tübüler atrofi, glomerüler hasar, vasküler konjesyon, vakuolizasyon ve interstisyel inflamasyona neden olan CP' nin etkilerine karşı koruyucu etkileri bulunmaktadır.

Anahtar Kelimeler:

Nefrotoksisite; siklofosfamid; sıçan; rosmarinik asit.

Effects of rosmarinic acid on cyclophosphamide-induced nephrotoxicity in rats

Purpose: Cyclophosphamide (CP) is an antineoplastic agent. It is used in the treatment of many types of cancer. Rosmarinic acid (RA) exhibits remarkable biological activities such as anti-inflammatory, antitumor, antibacterial, and antimicrobial effects. This study aimed to evaluate the effect of rosmarinic acid against CP-induced nephrotoxicity. Materials and Methods: Eighteen male Sprague Dawley rats were randomly divided into 3 equal groups; Sham group (n=6): 0.9% saline solution/8 days/oral gavage + 0.9% saline solution/8th day/intraperitoneal, CP group (n=6): 0.9% saline solution/8 days/oral gavage + 200 mg/kg/8th day/intraperitoneal CP, and CP+RA group (n=6): 100 mg/kg/8 days/oral gavage RA + 200 mg/kg/8th day/intraperitoneal CP was applied. Hematoxylin and Eosin, Periodic Acid-Schiff, and Masson’s Trichrome staining were performed on the collected tissues Results: Histopathological evaluation revealed tubular atrophy, glomerular damage, vascular congestion, vacuolization, and interstitial inflammation in the CP group. Histopathological scores were significantly lower in the CP+RA group compared to the CP group. Intertubular fibrosis was observed in the CP group compared to the Sham group. Fibrosis decreased with rosmarinic acid. PAS-stained sections from the CP group showed tubular epithelial vacuolization, brush border, and basal membrane disruption. These findings decreased with rosmarinic acid. The increased blood urea nitrogen level in the CP group was lower in the CP+RA group, while the decreased SOD level in the CP group was higher in the CP+RA group. Conclusion: RA has protective effects against CP causing tubular atrophy, glomerular damage, vascular congestion, vacuolization, and interstitial inflammation in the kidney

Keywords:

Nephrotoxicity, Cyclophosphamide, Rat Rosmarinic acid,

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Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6:638-47.
Fraiser LH, Kanekal S, Kehrer, JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs. 1991;42:781–95.
Swamy MK, Sinniah UR, Ghasemzadeh A. Anticancer potential of rosmarinic acid and its improved production through biotechnological interventions and functional genomics. Appl Microbiol Biotechnol. 2018;102:7775-93.
Swarup V, Ghosh J, Ghosh S, Saxena A, Basu A. Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob Agents Chemother. 2007;51:3367-70.
Ge L, Zhu M, Li X, Xu Y, Ma X, Shi R et al. Development of active rosmarinic acid-gelatin biodegradable films with antioxidant and long-term antibacterial activities. Food Hydrocoll. 2018;83:308-16.
Laura PF, Garzón MT, Vicente M. Relationship between the antioxidant capacity and effect of rosemary (Rosmarinus officinalis L.) polyphenols on membrane phospholipid order. J Agric Food Chem. 2010;58:161-71.
Cojocaru IM, Cojocaru M, Sapira V, Ionescu A. Evaluation of oxidative stress in patients with acute ischemic stroke. Rom J Intern Med. 2013;51:97-106.
Ijaz MU, Mustafa S, Batool R, Naz H, Ahmed H, Anwar H. Ameliorative effect of herbacetin against cyclophosphamide-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221132140.
Voelcker G. Causes and possibilities to circumvent cyclophosphamide toxicity. Anticancer Drugs. 2020;31:617-622.
Ahmed RA, Alam MF, Alshahrani S, Jali AM, Qahl AM, Khalid M, et al. Capsaicin ameliorates the cyclophosphamide-induced cardiotoxicity by ınhibiting free radicals generation, inflammatory cytokines, and apoptotic pathway in rats. Life (Basel). 2023;14;13:786.
Shanholtz C. Acute life-threatening toxicity of cancer treatment. Crit Care Clin. 2001;17:483-502.
Iqubal A, Iqubal MK, Sharma S, Ansari MA, Najmi AK, Ali SM et al. Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sci. 2019;218:112-31.
Saqib M, Khan B, Gul M, Yaseen S, Zaidi SU, Shareef M. Restoration of renal glutathione levels and histoarchitecture by N-acetylcysteine post cyclophosphamide exposure in rats. Pak J Physiol. 2019;15:33-7.
Sharma S, Sharma P, Kulurkar P, Singh D, Kumar D, Patial V. Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide-induced renal toxicity and peripheral neuropathy via PPAR-γ mediated inhibition of inflammation and apoptosis. Phytomedicine. 2017;36:108-17.
Dabla PK. Renal function in diabetic nephropathy. World J Diabetes. 2010;1:48-56.
Liu Q, Lin X, Li H, Yuan J, Peng Y, Dong L et al. Paeoniflorin ameliorates renal function in cyclophosphamide-induced mice via AMPK suppressed inflammation and apoptosis. Biomed Pharmacother. 2016;84:1899-905.
Abraham P, Indirani K, Sugumar E. Effect of cyclophosphamide treatment on selected lysosomal enzymes in the kidney of rats. Exp Toxicol Pathol. 2007;59:143-9.
Adikwu E, Nelson EC, Yambozibe AS. Comparative protective assessments of some antioxidants against cyclophosphamide-induced kidney toxicity in albino rats. J Nephropharmacol. 2019;8:1-8.
Cengiz M. Boric acid protects against cyclophosphamide-induced oxidative stress and renal damage in rats. Cell Mol Biol. 2018;64:11-4.
Weydert CJ, Cullen JJ. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc. 2010;5:51-66.
Chu X, Ci X, He J, Jiang L, Wei M, Cao Q, et al. Effects of a natural prolyl oligopeptidase inhibitor, rosmarinic acid, on lipopolysaccharide-induced acute lung injury in mice. Molecules. 2012;17:3586-98.
Sánchez-Campillo M, Gabaldon JA, Castillo J, BenaventeGarcía O, Del Baño MJ, Alcaraz M, et al. Rosmarinic acid, a photo-protective agent against UV and other ionizing radiations. Food Chem Toxicol. 2009;47:386-92.
Al-Dhabi NA, Arasu MV, Park CH, Park SU. Recent studies on rosmarinic acid and its biological and pharmacological activities. Excli J. 2014;13:1192-5.
Tavafi M, Ahmadvand H, Khalatbari A, Tamjidipoor A. Rosmarinic acid ameliorates diabetic nephropathy in uninephrectomized diabetic rats. Iran J Basic Med Sci. 2011;14:275-83.
Bayomy NA, Elbakary RH, Ibrahim MAA, Abdelaziz EZ. Effect of lycopene and rosmarinic acid on gentamicin ınduced renal cortical oxidative stress, apoptosis, and autophagy in adult male albino rat. Anat Rec. 2017;300:1137-49.
Murakami K, Haneda M, Qiao S, Naruse M, Yoshino M. Prooxidant action of rosmarinic acid: Transition metal-dependent generation of reactive oxygen species. Toxicol In Vit. 2007;21:613-7.
Muñoz-Muñoz JL, Garcia-Molina F, Ros E, Tudela J, García-Canovas F, Rodriguez-Lopez JN. Prooxidant and antioxidant activities of rosmarinic acid. J Food Biochem. 2013;37:396–408.