Evaluation of the anti-inflammatory effect of chromium picolinate in methotrexate induced nephrotoxicity rat model

Year 2025, Volume: 29 Issue: 4, 1608 - 1615, 05.07.2025

Jehan Najm Aldeen Farhan Ali Faris Hassan

https://doi.org/10.12991/jrespharm.1734542

Abstract

Methotrexate is a folate antimetabolite chemical used to treat many forms of cancer and cleared mainly by kidney which result in a nephrotoxicity as a major complication of methotrexate. Trivalent chromium complex, chromium picolinate (CrPic), is mostly utilized to regulate glucose and raise insulin sensitivity—particularly in diabetes. The objective of this study was to assess the renoprotective effects of Chromium in mitigating nephrotoxicity induced by Methotrexate in rats. Study conducted on 32 male rats divided into 4 groups; Group I (Control group) in which rats received distilled water orally for 8 days, Group II (Induction group) which received a single intraperitoneal injection of Methotrexate (20 mg/kg) on the first day Followed by distilled water for 7 days, Group III (Chromium 2mg) which received a single intraperitoneal injection of Methotrexate (20 mg/kg) on the first day Followed by CrPic at a dose (2mg/kg) orally for 7 days and finally group IV which is similar to Group III except that the dose of CrPic is 4mg/kg. The levels of creatinine, Kidney Injury Molecule-1 (KIM-1), interleukin 1 beta (IL-1β), and tumor necrosis factors-α (TNF-α) were evaluated for all studied groups and the results showed that the administration of CrPic caused a significant decrease (p<0.05) in the levels of creatinine, KIM-1, IL-1β, and TNF-α compared to methotrexate-treated rats and the levels of these markers rturned to levels comparable to those of controls. In conclusion, the administration of CrPic exhibits renoprotective and anti-inflammatory effects and may reduce the risk of methotrexate-induced nephrotoxicity.

Keywords

Interleukin-1 beta , tumor necrosis factors , kidney injury molecule-1 , methotrexate induced nephrotoxicity , chromium picolinate , tumor necrosis factor-alpha

References

• [1] Luft FC. Biomarkers and predicting acute kidney injury. Acta Physiol (Oxf). 2021;231(1):e13479. https://doi.org/10.1111/apha.13479
• [2] Kwiatkowska E, Doma.ski L, Dziedziejko V, Kajdy A, Stefa.ska K, Kwiatkowski S. The mechanism of drug nephrotoxicity and the methods for preventing kidney damage. Int J Mol Sci. 2021;22(11):6109. https://doi.org/10.3390/ijms22116109
• [3] Alum EU, Famurewa AC, Orji OU, Aja PM, Nwite F, Ohuche SE, Ukasoanya SC, Nnaji LO, Joshua D, Igwe KU, Chima SF. Nephroprotective effects of Datura stramonium leaves against methotrexate nephrotoxicity via attenuation of oxidative stress-mediated inflammation and apoptosis in rats. Avicenna J Phytomed. 2023;13(4):377-387. https://doi.org/10.22038%2FAJP.2023.21903
• [4] Yang YY, Gao L, Ding N, Wang XB, Zhang LP, Gao LH, Wang Z. How to rescue high-dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration? Pak J Pharm Sci. 2020;33(3):1163-1167.
• [5] Mahmoud AM , Hussein OE , Abd El-Twab SM , Hozayen WG . Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARƒÁ, and suppression of NF-ƒÈB/NLRP3 inflammasome axis. Food Funct. 2019;10(8):4593-4607. https://doi.org/10.1039/c9fo00114j
• [6] Hamed KM, Dighriri IM, Baomar AF, Alharthy BT, Alenazi FE, Alali GH, Alenazy RH, Alhumaidi NT, Alhulayfi DH, Alotaibi YB, Alhumaidan SS, Alhaddad ZA, Humadi AA, Alzahrani SA, Alobaid RH. Overview of methotrexate toxicity: A comprehensive literature review. Cureus. 2022;14(9):e29518. https://doi.org/10.7759/cureus.29518
• [7] Heidari R, Ahmadi A, Mohammadi H, Ommati MM, Azarpira N, Niknahad H. Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomed Pharmacother. 2018;107:834-840. https://doi.org/10.1016/j.biopha.2018.08.050
• [8] Abd El-Twab SM, Hussein OE, Hozayen WG, Bin-Jumah M, Mahmoud AM. Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-ƒÈB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling. Inflamm Res. 2019;68(6):511-523. https://doi.org/10.1007/s00011-019-01241-z
• [9] Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gulcin .. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017;41(5):e12398. https://doi.org/10.1111/jfbc.12398
• [10] Danwilai K, Konmun J, Sripanidkulchai B, Subongkot S. Antioxidant activity of ginger extract as a daily supplement in cancer patients receiving adjuvant chemotherapy: a pilot study. Cancer Manag Res. 2017;9:11-18. https://doi.org/10.2147/cmar.s124016
• [11] Talab AT, Abdollahzad H, Nachvak SM, Pasdar Y, Eghtesadi S, Izadi A, Aghdashi MA, Mohammad Hossseini Azar MR, Moradi S, Mehaki B, Moradi S. Effects of chromium picolinate supplementation on cardiometabolic biomarkers in patients with Type 2 Diabetes Mellitus: A randomized clinical trial. Clin Nutr Res. 2020;9(2):97-106. https://doi.org/10.7762/cnr.2020.9.2.97
• [12] Tarrahi MJ, Tarrahi MA, Rafiee M, Mansourian M. The effects of chromium supplementation on lipidprofile in humans: A systematic review and meta-analysis ofrandomized controlled trials. Pharmacol Res. 2021;164:105308. https://doi.org/10.1016/j.phrs.2020.105308
• [13] Moradi F, Kooshki F, Nokhostin F, Khoshbaten M, Bazyar H, Pourghassem Gargari B. A pilot study of the effects of chromium picolinate supplementation on serum fetuin-A, metabolic and inflammatory factors in patients with nonalcoholic fatty liver disease: A double-blind, placebo-controlled trial. J Trace Elem Med Biol. 2021;63:126659. https://doi.org/10.1016/j.jtemb.2020.126659
• [14] Imanparast F, Javaheri J, Kamankesh F, Rafiei F, Salehi A, Mollaaliakbari Z, Rezaei F, Rahimi A, Abbasi E. The effects of chromium and vitamin D3 co-supplementation on insulin resistance and tumor necrosis factor-alpha in type 2 diabetes: a randomized placebo-controlled trial. Appl Physiol Nutr Metab. 2020;45(5):471-477. https://doi.org/10.1139/apnm-2019-0113
• [15] Zhang X, Cui L, Chen B, Xiong Q, Zhan Y, Ye J, Yin Q. Effect of chromium supplementation on hs-CRP, TNF-α and IL-6 as risk factor for cardiovascular diseases: A meta-analysis of randomized-controlled trials. Complement Ther Clin Pract. 2021;42:101291. https://doi.org/10.1016/j.ctcp.2020.101291
• [16] Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A, Shah P. Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center. Clin J Am Soc Nephrol. 2013;8(3):347-354. https://doi.org/10.2215/cjn.03530412
• [17] Sahindokuyucu-Kocasari F, Akyol Y, Ozmen O, Erdemli-Kose SB, Garli S. Apigenin alleviates methotrexate-induced liver and kidney injury in mice. Hum Exp Toxicol. 2021;40(10):1721-1731. https://doi.org/10.1177/09603271211009964
• [18] Shah BK, Seth R, Sinha A, Gupta AK, Meena JP. Acute kidney injury in methotrexate treated leukemia. J BP Koirala Inst Health Sci. 2023;6(2):23–28. https://doi.org/10.3126/jbpkihs.v6i2.55836.
• [19] Jana S, Mitra P, Dutta A, Khatun A, Kumar Das T, Pradhan S, Kumar Nandi D, Roy S. Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model. Curr Res Toxicol. 2023;5:100135. https://doi.org/10.1016%2Fj.crtox.2023.100135
• [20] Abdel-Raheem IT, Khedr NF. Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(4):341-453. https://doi.org/10.1007/s00210-013-0949-x
• [21] Kirbas A, Cure MC, Kalkan Y, Cure E, Tumkaya L, Sahin OZ, Yuce S, Kizilkaya B, Pergel A. Effect of infliximab on renal injury due to methotrexate in rat. Iran J Kidney Dis. 2015;9(3):221-229.
• [22] Alduboni NM, Al-Shawi NN. Possible protective effects of two different doses of cyanocobalamin against methotrexate nephrotoxicity model in rats. Iraqi J Pharm Sci. 2022;31(2):211–217. https://doi.org/10.31351/vol31iss2pp212-217
• [23] Arab HH, Abd El-Aal SA, Eid AH, Arafa EA, Mahmoud AM, Ashour AM. Targeting inflammation, autophagy, and apoptosis by troxerutin attenuates methotrexate-induced renal injury in rats. Int Immunopharmacol. 2022;103:108284. https://doi.org/10.1016/j.intimp.2021.108284
• [24] Qi SS, Zheng HX, Jiang H, Yuan LP, Dong LC. Protective effects of chromium picolinate against diabetic-ınduced renal dysfunction and renal fibrosis in streptozotocin-ınduced diabetic rats. Biomolecules. 2020;10(3):398. https://doi.org/10.3390%2Fbiom10030398
• [25] Mozaffari MS, Baban B, Abdelsayed R, Liu JY, Wimborne H, Rodriguez N, Abebe W. Renal and glycemic effects of high-dose chromium picolinate in db/db mice: assessment of DNA damage. J Nutr Biochem. 2012;23(8):977-985. https://doi.org/10.1016%2Fj.jnutbio.2011.05.004
• [26] Sheikhhossein F, Amini MR, Shahinfar H, Djafari F, Safabakhsh M, Shab-Bidar S, Effects of chromium supplementation on inflammatory biomarkers: A systematic review and dose-response meta-analysis of randomized controlled trials. Eur J Integr Med. 2020;37:101147. https://doi.org/10.1016/j.eujim.2020.101147
• [27] Moradi F, Maleki V, Saleh-Ghadimi S, Kooshki F, Pourghassem Gargari B. Potential roles of chromium on inflammatory biomarkers in diabetes: A Systematic. Clin Exp Pharmacol Physiol. 2019;46(11):975-983. https://doi.org/10.1111/1440-1681.13144.
• [28] Moradi F, Kooshki F, Nokhostin F, Khoshbaten M, Bazyar H, Pourghassem Gargari B. A pilot study of the effects of chromium picolinate supplementation on serum fetuin-A, metabolic and inflammatory factors in patients with nonalcoholic fatty liver disease: A double-blind, placebo-controlled trial. J Trace Elem Med Biol. 2021;63:126659. https://doi.org/10.1016/j.jtemb.2020.126659
• [29] Morsy MA, El-Sheikh AAK, Abdel-Hafez SMN, Kandeel M, Abdel-Gaber SA. Paeonol protects against methotrexate-ınduced nephrotoxicity via upregulation of P-gp expression and ınhibition of TLR4/NF-κB pathway. Front Pharmacol. 2022;13:774387. https://doi.org/10.3389/fphar.2022.774387
• [30] Liu Y, Wang D. Administration of chromium(III) and manganese(II) as a potential protective approach against daunorubicin-induced cardiotoxicity: in vitro and in vivo experimental evidence. Biol Trace Elem Res. 2013;156(1-3):253-261. https://doi.org/10.1007/s12011-013-9851-0
• [31] Aledani AHE, Khudhair NA, Alrafas R. Effect of different methods of anesthesia on physio-biochemical parameters in laboratory male rats. Basra J Vet Res. 2020;19(1):206-214
• [32] Greenfield EA. Sampling and preparation of mouse and rat serum. Cold Spring Harb Protoc. 20171;2017(11):pdb.prot100271. https://doi.org/10.1101/pdb.prot100271
• [33] Mahmood SH, Hassan AF. The protective effect of omega-7 on cisplatin-induced nephrotoxicity in rat model. Iraqi J Pharm Sci. 2023;32(2):128–133. https://doi.org/10.31351/vol32iss2pp128-133
• [34] Robinson N, Ganesan R, Hegedűs C, Kovács K, Kufer TA, Virág L. Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos. Redox Biol. 2019;26:101239. https://doi.org/10.1016/j.redox.2019.101239
• [35] Mahmood YS, Kadhim SH. Protective effects of citronellol against rhabdomyolysis-induced acute kidney injury in mice by inhibiting NF-κB and IL-1β signaling pathway. Iraqi J Pharm Sci. 2023;32:85–90. https://doi.org/10.31351/vol32issSuppl.pp85-90
• [36] Aldossary SA. Protective effect of hesperidin against methotrexate-ınduced nephrotoxicity in rats. Life Sci J 2019;16(2):18-22. https://doi.org/10.7537/marslsj160219.04
• [37] Manna MJ, Baqir LS, Abdulamir HA. The assessment of the antimicrobial effect of gemfibrozil alone or in combination with ceftriaxone or gentamycin on several types of bacteria. Acta Pharm. Sci. 2024;62(3):565-574. http://dx.doi.org/10.23893/1307-2080.APS6235.
• [38] Al-Shammari AH, Abbood ZA, Lateef HF. Assessing the impacts of L-carnitine and modafinil on fatigue in Iraqi multiple sclerosis patients. J Adv Pharm Technol Res. 2023;14(3):226-228. https://doi.org/10.4103%2FJAPTR.JAPTR_225_23