Ethanolic extract of Iris songarica rhizome attenuates methotrexate-induced liver and kidney damages in rats

Document Type : Original Research Article


1 Department of Anatomical Sciences, Birjand University of Medical Sciences, Birjand, Iran

2 Cellular and Molecular Research Center, Department of Anatomical Sciences, Birjand University of Medical Sciences, Birjand, Iran

3 Cellular and Molecular Research Center, Department of Pharmacology, Birjand University of Medical Sciences, Birjand, Iran

4 Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran


Objective: The long-term sequelae of methotrexate (MTX) remain the major cause of concern for both patients and therapists. Therefore, new approaches to decrease MTX side effects are needed. The study was carried out to evaluate the effects of Iris songarica Schrenk (IS) rhizome extract against MTX-induced hepatic and renal injuries in rats.
Materials and Methods: Forty male Wistar rats were randomly divided into five groups (n=8) including control, MTX, IS50, IS150 and IS300. Control and MTX groups were only treated orally with saline; whereas, IS50, IS150 and IS300 groups were treated with IS extract at three different doses (50, 150, and 300 mg/kg, respectively). Besides, the MTX and experimental groups were received a single dose of MTX (20 mg/kg) intraperitoneally on day 4. On the ninth day, animals were sacrificed, blood transaminases, urea and creatinine were assessed and the concentration of malondialdehyde (MDA) and the activity of super-oxide dismutase (SOD) were determined in both liver and kidney tissues. Moreover, hepatic and renal damages were evaluated histopathologically.
Results: MTX by increasing oxidative stress (MDA) and decreasing antioxidant capacity (SOD) induced hepatic and renal damages as confirmed by biochemical and histological parameters analyses. However, treatment with IS caused significant improvements in hepatic and renal histological architectures and SOD activity (p<0.01) along with reducing liver enzymes, urea, creatinine and MDA (p<0.01).
Conclusion: The results of the present study showed that IS extract through antioxidant and probably anti-inflammatory activities, could effectively limit MTX-induced hepatic and renal injuries in rats.


Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. 2017. Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. Oxid Med Cell Longev, 2017:3281670.
Ahani A, Hassanzadeh-Taheri M, Hosseini M, Hassanpour-Fard M. 2017. Antinociceptive and anti-inflammatory activities of Iris songarica schrenk rhizome ethanolic extract in mice. J Arak Uni Med Sci, 20:9-19.
Akther N, Andrabi K, Nissar A, Ganaie S, Chandan BK, Gupta AP, Khuswant M, Sultana S, Shawl AS. 2014. Hepatoprotective activity of LC–ESI-MS standardized Iris spuria rhizome extract on its main bioactive constituents. Phytomedicine, 21:1202-1207.
Asci H, Ozmen O, Ellidag HY, Aydin B, Bas E, Yilmaz N. 2017. The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal, 25:890-897.
Ataie Z, Mehrani H, Ghasemi A, Farrokhfall K. 2019. Cinnamaldehyde has beneficial effects against oxidative stress and nitric oxide metabolites in the brain of aged rats fed with long-term, high-fat diet. J Funct Foods, 52:545-551.
Ayatollahi SA, Moein MR, Kobarfard F, Choudhary MI. 2004. Two isoflavones from Iris songarica Schrenk. Daru,12:54-57.
Becciolini A, Biggioggero M, Favalli EG. 2016. The role of methotrexate as combination therapy with etanercept in rheumatoid arthritis: Retrospective analysis of a local registry. J Int Med Res, 44:113-118.
Bu T, Wang C, Meng Q, Huo X, Sun H, Sun P, Zheng S, Ma X, Liu Z, Liu K. 2018. Hepatoprotective effect of rhein against methotrexate-induced liver toxicity. Eur J Pharmacol, 834:266-273.
Bertino JR. 2000. Methotrexate: historical aspects. In: Cronstein BN, Bertino JR (Eds), Methotrexate, pp. 1-7, Basel, Birkhäuser.
De S, Kundu S, Chatterjee U, Chattopadhyay S, Chatterjee M. 2018. Allylpyrocatechol attenuates methotrexate-induced hepatotoxicity in a collagen-induced model of arthritis. Free Radic Res, 52:698-711.
El-Twab SMA, Hussein OE, Hozayen WG, Bin-Jumah M, Mahmoud AM. 2019. Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling. Inflamm Res, 68:511-523.
Hassanzadeh-Taheri M, Hassanpour-Fard M, Doostabadi M, Moodi H, Vazifeshenas-Darmiyan K, Hosseini M. 2018a. Co-administration effects of aqueous extract of turnip leaf and metformin in diabetic rats. J Tradit Complement Med, 8:178-183.
Hassanzadeh-Taheri M, Hosseini M, Hassanpour-Fard M, Ghiravani Z, Vazifeshenas-Darmiyan K, Yousefi S, Ezi S. 2016. Effect of turnip leaf and root extracts on renal function in diabetic rats. Orient Pharm Exp Med, 16:279-286.
Hassanzadeh-Taheri M, Hosseini M, Salimi M, Moodi H, Dorranipour D. 2018b. Acute and sub-acute oral toxicity evaluation of Astragalus hamosus seedpod ethanolic extract in Wistar rats. Pharmaceutical Sciences, 24:23-30.
Heidari R, Ahmadi A, Mohammadi H, Ommati MM, Azarpira N, Niknahad H. 2018. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomed Pharmacother, 107:834-840.
Kalantari H, Asadmasjedi N, Reza Abyaz M, Mahdavinia M, Mohammadtaghvaei N. 2019. Protective effect of inulin on methotrexate-induced liver toxicity in mice. Biomed Pharmacother, 110:943-950.
Khafaga AF, El-Sayed YS. 2018. Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation. Life Sci, 196:9-17.
King C, Killens WR. 2012. A guide to species irises: their identification and cultivation.pp.200, Cambridge, Cambridge University Press.
Kurutas EB. 2016. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J, 15:71.
Maestá I, Nitecki R, Horowitz NS, Goldstein DP, de Freitas Segalla Moreira M, Elias KM, Berkowitz RS. 2018. Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience. Gynecol Oncol, 148:161-167.
Mehrzadi S, Fatemi I, Esmaeilizadeh M, Ghaznavi H, Kalantar H, Goudarzi M. 2018. Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats. Biomed Pharmacother, 97:233-239.
Moein MR, Khan SI, Ali Z, Ayatollahi SA, Kobarfard F, Nasim S, Choudhary MI, Khan IA. 2008. Flavonoids from Iris songarica and their antioxidant and estrogenic activity. Planta med, 74:1492-1495.
Moghadam AR, Tutunchi S, Namvaran-Abbas-Abad A, Yazdi M, Bonyadi F, Mohajeri D, Mazani M, Marzban H, Łos MJ, Ghavami S. 2015. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC Complement Altern Med, 15:246.
Nurgali K, Jagoe RT, Abalo R. 2018. Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Front Pharmacol,9:245.
Ozogula B, Kisaoglua A, Turanb MI, Altunerc D, Senerd E, Cetine N, Ozturke C. 2013. The effect of mirtazapine on methotrexate-induced toxicity in rat liver. Sci Asia 39:356-336.
Pour MG, Mirazi N, Seif A. 2019. Treatment of liver and spleen illnesses by herbs: Recommendations of Avicenna’s heritage" Canon of Medicine". Avicenna J Phytomed, 9:101.
Shah VV, Lin EJ, Reddy SP, Wu JJ. 2016. Chapter 4 - Methotrexate. In: Wu JJ, Feldman SR, Lebwohl MG (Eds), Therapy for Severe Psoriasis, pp. 37-48, Elsevier.
Taylor P, Balsa Criado A, Mongey A-B, Avouac J, Marotte H, Mueller RB. 2019. How to get the most from methotrexate (MTX) treatment for your rheumatoid arthritis patient? MTX in the treat-to-target strategy. J Clin Med, 8:515.
Weinblatt ME. 2018. Methotrexate: who would have predicted its importance in rheumatoid arthritis? Arthritis Res Ther, 20:103-103.
Xu Q, Higgins T, Cembrowski GS. 2015. Limiting the testing of AST: a diagnosticallynonspecific enzyme. Am J Clin Pathol, 144:423-426.
Zhang J, Chen R, Yu Z, Xue L. 2016. Superoxide dismutase (SOD) and catalase (CAT) activity assay protocols for caenorhabditis elegans. Bio protocol, 7: e2505.