Levocabastine ameliorates cyclophosphamide-induced nephrotoxicity in Swiss albino mice via NF-κB/cleaved caspase-3/TGF-β signaling pathways

Abstract

Cyclophosphamide (CP) is a potent anticancer drug, but nephrotoxicity is one of the vital organ toxicities that it causes as a side effect. We tried to evaluate the nephroprotective effect of levocabastine (LEV) in CP-induced nephrotoxicity in Swiss albino mice. Mice were given CP 200 mg/kg, i.p., once on the 7^th day. LEV (0.05 and 0.1 mg/kg, i.p.) and fenofibrate (FF) (80 mg/kg, p.o.) were given daily for 14 days. On the 15^th day, animals were sacrificed and kidneys were removed for examination. The docking study showed significant binding of LEV and FF against TGF-β1, which is a prime target molecule involved in nephrotoxicity. CP 200 group showed nephrotoxicity in terms of oxidative stress, apoptosis, inflammation, and fibrosis as manifested by decreased levels of SOD, catalase, GSH, blood urea nitrogen/creatinine (BUN/Cr) ratio, and increased TBARS, nitrite, TNF-α, IL-6, TGF-β1, IL-1β, urea, uric acid, creatinine, and BUN. A decrease in body weight (BW) and an increase in kidney weight (KW) with an increased KW/BW ratio was also observed. Cleaved caspase-3 and NF-κB expression was also increased. Histopathological aberrations, like renal corpuscle damage, Bowman’s space widening, glomerulus, mesangium cell disintegration, atrophic podocytes, vacuolation, and fibrotic changes were also seen. LEV 0.1 and FF 80 significantly reversed these changes toward normal and showed nephroprotective potential. Thus, seeing the protective effect of LEV on CP-intoxicated mice, we conclude that LEV may be used as an adjuvant with CP in cancer, however, it needs more studies with the direct cancer model to confirm the claim.

Keywords

renal toxicity - levocabastine - cyclophosphamide - oxidative stress - renal inflammation - fenofibrate

Publication History

Received: 26 September 2024

Accepted: 24 February 2025

Article published online:
14 April 2025

• References

• 1 Uyumlu AB, Satılmış B, Atıcı B. et al. Phenethyl factor isothiocyanate protects against cyclophosphamide-induced nephrotoxicity via nuclear E2–related factor 2 pathway in rats. Experimental Biology and Medicine 2023; 248: 157-164
• 2 Jeelani R, Khan SN, Shaeib F. et al. Cyclophosphamide and acrolein induced oxidative stress leading to deterioration of metaphase II mouse oocyte quality. Free Radical Biology and Medicine 2017; 110: 11-18
• 3 Jomova K, Alomar SY, Alwasel SH. et al. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Archives of Toxicology 2024; 98: 1323-1367
• 4 Temel Y, Kucukler S, Yıldırım S. et al. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn-Schmiedeberg’s archives of pharmacology 2020; 393: 325-337
• 5 Alaqeel NK, Al-Hariri MT. Naringenin ameliorates Cyclophosphamide-induced nephrotoxicity in experimental model. Saudi Journal of Biological Sciences 2023; 30: 103674
• 6 Iqubal A, Najmi AK, Md S. et al. Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules. Drug Delivery 2023; 30: 2241661
• 7 Alshahrani S, Ali Thubab HM, Ali Zaeri AM. et al. The protective effects of sesamin against cyclophosphamide-induced nephrotoxicity through modulation of oxidative stress, inflammatory-cytokines and apoptosis in rats. International Journal of Molecular Sciences 2022; 23: 11615
• 8 Ayza MA, Zewdie KA, Yigzaw EF. et al. Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity. International Journal of Nephrology 2022; 2022: 5096825
• 9 Jiang X, Ren Z, Zhao B. et al. Ameliorating effect of pentadecapeptide derived from cyclina sinensis on cyclophosphamide-induced nephrotoxicity. Marine drugs 2020; 18: 462
• 10 Jin L, Hua H, Ji Y. et al. Anti-inflammatory role of fenofibrate in treating diseases. Biomolecules and Biomedicine 2023; 23: 376
• 11 Akram W, Najmi AK, Alam MM. et al. Levocabastine ameliorates cyclophosphamide-induced cardiotoxicity in Swiss albino mice: Targeting TLR4/NF-κB/NLRP3 signaling pathway. Toxicology and Applied Pharmacology 2024; 483: 116838
• 12 Refaie MMM. Upregulation of peroxisome proliferator activated receptor alpha by fenofibrate in induced testicular ischemia reperfusion. Biomedicine & Pharmacotherapy 2018; 98: 507-515
• 13 Almutairi FM, Ajmal MR, Siddiqi MK. et al. Biophysical insight into the interaction of levocabastine with human serum albumin: spectroscopy and molecular docking approach. Journal of Biomolecular Structure and Dynamics 2021; 39: 1525-1534
• 14 Szelenyi I. Allergic rhinitis: meaningful and less meaningful combination treatments including reminiscences. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2014; 69: 414-416
• 15 Baiula M, Bedini A, Carbonari G. et al. Therapeutic targeting of eosinophil adhesion and accumulation in allergic conjunctivitis. Frontiers in Pharmacology 2012; 3: 203
• 16 Pozdnyakov DI, Khadzieva ZD, Pozdnyakova AE. et al. Antiallergical effect of new combined nazal aerodisperse system in the conditions of experimental allergic rhinitis. Biomedical and Pharmacology. Journal 2019; 12: 453-461
• 17 Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974; 47: 469-474
• 18 Claiborne A. Handbook of methods for oxygen radical research. Florida: CRC Press, Boca Raton; 1985: 283-284
• 19 Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Analytical biochemistry 1968; 25: 192-205
• 20 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical biochemistry 1979; 95: 351-358
• 21 Sastry KV, Moudgal RP, Mohan J. et al. Spectrophotometric determination of serum nitrite and nitrate by copper–cadmium alloy. Analytical biochemistry 2002; 306: 79-82
• 22 Lowry OH, Rosebrough NJ, Farr AL. et al. Protein measurement with the Folin phenol reagent. The Journal of biological chemistry 1951; 193: 265-275
• 23 Hayashi I, Tome Y, Shimosato Y. Thiosemicarbazide used after periodic acid makes methenamine silver staining of renal glomerular basement membranes faster and cleaner. Stain Technology 1989; 64: 185-190
• 24 Santos ML, de Brito BB, da Silva FA. et al. Nephrotoxicity in cancer treatment: An overview. World journal of clinical oncology 2020; 11: 190
• 25 Mahipal P, Pawar RS. Nephroprotective effect of Murraya koenigii on cyclophosphamide induced nephrotoxicity in rats. Asian Pacific journal of tropical medicine 2017; 10: 808-812
• 26 Kim SH, Lee IC, Baek HS. et al. Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food and Chemical Toxicology 2014; 64: 110-118
• 27 Nafees S, Rashid S, Ali N. et al. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chemico-biological interactions 2015; 231: 98-107
• 28 Zheng Y, Yi H, Zhan Z. et al. Reactive oxygen/nitrogen species scavenging and inflammatory regulation by renal-targeted bio-inspired rhodium nanozymes for acute kidney injury theranostics. Journal of Colloid and Interface Science 2024; 662: 413-425
• 29 Abraham P, Rabi S. Aminoguanidine, a selective nitric oxide synthase inhibitor, attenuates cyclophosphamide-induced renal damage by inhibiting protein nitration and poly (ADP-Ribose) polymerase activation. Chemotherapy 2011; 57: 327-334
• 30 Fouad AA, Abdel-Gaber SA, Abdelghany MI. Hesperidin opposes the negative impact of cyclophosphamide on mice kidneys. Drug and Chemical Toxicology 2021; 44: 223-228
• 31 Rehman MU, Tahir M, Ali F. et al. Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: the protective effect of Ellagic acid. Molecular and Cellular Biochemistry 2012; 365: 119-127
• 32 Ma CH, Kang LL, Ren HM. et al. Simiao pill ameliorates renal glomerular injury via increasing Sirt1 expression and suppressing NF-κB/NLRP3 inflammasome activation in high fructose-fed rats. Journal of ethnopharmacology 2015; 172: 108-117
• 33 Waz S, Heeba GH, Hassanin SO. et al. Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway. Life Sciences 2021; 264: 118630
• 34 Shen J, Dai Z, Li Y. et al. TLR9 regulates NLRP3 inflammasome activation via the NF-kB signaling pathway in diabetic nephropathy. Diabetology & metabolic syndrome 2022; 14: 26
• 35 Ma T-T, Meng X-M. TGF-β/Smad and renal fibrosis. Renal Fibrosis: Mechanisms and Therapies 2019; 347-364
• 36 Meng J, Li L, Zhao Y. et al. MicroRNA-196a/b mitigate renal fibrosis by targeting TGF-β receptor 2. Journal of the American Society of Nephrology: JASN 2016; 27: 3006
• 37 Portilla D. Apoptosis, fibrosis and senescence. Nephron Clinical Practice 2014; 127: 65-69
• 38 Adeyemi OS, Elebiyo TC. Moringa oleifera supplemented diets prevented nickel-induced nephrotoxicity in wistar rats. Journal of nutrition and metabolism 2014; 2014: 958621
• 39 Ayza MA, Rajkapoor B, Wondafrash DZ. et al. Protective effect of Croton macrostachyus (euphorbiaceae) stem bark on cyclophosphamide-induced nephrotoxicity in rats. Journal of Experimental Pharmacology 2020; 275-283
• 40 Shafi M, Shah SA, Bashir SM. et al. Nephro-Pathological hallmarks for the investigation of metformin induced sub-acute toxicity in Wister rats. 2023; 12: 4248-4255
• 41 Dobrek L, Baranowska A, Skowron B. et al. Biochemical and histological evaluation of kidney function in rats after a single administration of cyclophosphamide and ifosfamide. J Nephrol Kidney Dis 2017; 1: 1002-1008
• 42 de Haan K, Zhang Y, Zuckerman JE. et al. Deep learning-based transformation of H&E stained tissues into special stains. Nature communications 2021; 12: 4884
• 43 Yu X, Lan P, Feng J. et al. Renal amyloidosis complicated by light chain deposition nephropathy: a case report. International Journal of Clinical and Experimental Pathology 2019; 12: 2279
• 44 Agarwal SK, Sethi S, Dinda AK. Basics of kidney biopsy: A nephrologist’s perspective. Indian journal of nephrology 2013; 23: 243-252
• 45 Chou JY, Mansfield BC, Weinstein DA. Renal disease in type I glycogen storage disease. In: Genetic Diseases of the Kidney. Elsevier; 2009: 693-708
• 46 Mokhtari T, Osman HE, El-Kenawy AE. et al. Ameliorative effect of virgin olive oil against nephrotoxicity following sub-chronic administration of ethephon in male rats. Journal of traditional and complementary medicine 2020; 10: 487-495
• 47 Cossey LN, Dvanajscak Z, Larsen CP. A diagnostician’s field guide to crystalline nephropathies. Seminars in Diagnostic Pathology 2020; 37: 135-142
• 48 Naylor RW, Morais MR, Lennon R. Complexities of the glomerular basement membrane. Nature Reviews Nephrology 2021; 17: 112-127