Abstract
Objective: To investigate the effect of levo-carnosine co-administration on portal inflammation and fibrotic alterations caused by cisplatin in the BALB/c mice liver.
Methods: The study was carried out from December 2020 to April 2022 at the Department of Anatomy in collaboration with the Department of Physiology, Army Medical College in Rawalpindi. The study included 90 adult BALB/c mice; three groups of 30 mice each. Group A (Control) was not given any medication. Group B (Cisplatin) received intraperitoneal cisplatin 8mg/kg body weight as a single weekly dose for four weeks, whereas Group C (Carnosine + Cisplatin) administered similar cisplatin treatment along with levo-carnosine 300mg/kg body weight every day by oral lavage. Mice were then euthanized, a 2 ml of terminal blood sample was obtained by intracardiac puncture for biochemical analysis, and then the liver was dissected out, processed, and stained with Hematoxylin and Eosin (H&E) and Masson’s trichrome stains to study portal inflammation and fibrosis, respectively.
Results: Absence of portal inflammation was observed in 86.7% of mice in group A, moderate to severe portal inflammation was seen in 66.7% specimens in group B, whereas mild portal inflammation was observed in 43.3% of specimens in group C. Group B shows significantly (p<0.001) raised portal inflammation among the three groups. Similarly, liver fibrosis was not seen in 93.3% of mice in group A, mild to moderate fibrosis was seen in 83.3% specimens in group B, whereas mild fibrosis was noted in 26.7% of mice in group C. Group-C shows significantly (p<0.001) high liver fibrosis among the three groups. The serum albumin mean was 2.36±0.12 g/dl, 1.71±0.12 g/dl, and 2.16±0.26 g/dl in group A, group B, and group C, respectively. A significant (p<0.001) decrease in serum albumin was observed in group B when associated with group A and group C.
Conclusion: Cisplatin administration caused portal inflammation and fibrosis in the liver of mice. Levo-carnosine, when administered along with cisplatin, reduced the toxic effect of cisplatin on the mice's liver.
Keywords: Antioxidants, Carnosine; Cisplatin; Inflammation; Liver disease.
References
Björnsson H, Björnsson E. Drug-induced liver injury: pathogenesis, epidemiology, clinical features, and practical management. Eur J Intern Med. 2022; 97:26-31. https://doi.org/10.1016/j.ejim.2021.10.035
Zhang CJ, Meyer SR, O’Meara MJ, Huang S, Capeling MM, Ferrer-Torres D, et al. A human liver organoid screening platform for DILI risk prediction. J Hepatol. 2023; 78(5):998-1006. https://doi.org/10.1016/j.jhep.2023.01.019
Ali S, Rasul A, Latif N, Aleem SB, Zia R, Khan B. Effect of levo-carnosine on biomarkers of oxidative stress and hepatotoxicity in cisplatin-treated male Sprague Dawley rats. Pak Armed Forces Med J. 2022; 72(4):1334-8.
Habib SA, Suddek GM, Rahim MA, Abdelrahman RS. The protective effect of protocatechuic acid on hepatotoxicity induced by cisplatin in mice. Life Sci. 2021; 277:119485. https://doi.org/10.1016/j.lfs.2021.119485
Sherif IO. Hepatoprotective effect of arjunolic acid against cisplatin-induced hepatotoxicity: Targeting oxidative stress, inflammation, and apoptosis. J Biochem Mol Toxicol. 2021; 35(4):e22714. https://doi.org/10.1002/jbt.22714
Taghizadeh F, Hosseinimehr SJ, Zargari M, Karimpour Malekshah A, Mirzaei M, Talebpour Amiri F. Alleviation of cisplatin‐induced hepatotoxicity by gliclazide: Involvement of oxidative stress and caspase‐3 activity. Pharmacol Res Perspect. 2021; 9(3):e00788. https://doi.org/10.1002/prp2.788
Wang Q, Sadati S, Kabthymer RH, Gadanec LK, Lawton A, Tripodi N, et al. The impact of carnosine on biological ageing–A geroscience approach. Maturitas. 2024; 189:108091. https://doi.org/10.1016/j.maturitas.2024.108091
Cesak O, Vostalova J, Vidlar A, Bastlova P, Student V Jr. Carnosine and beta-alanine supplementation in human medicine: narrative review and critical assessment. Nutrients. 2023; 15(7):1770. https://doi.org/10.3390/nu15071770
Jukić I, Kolobarić N, Stupin A, Matić A, Kozina N, Mihaljević Z, et al. Carnosine, small but mighty—prospect of use as a functional ingredient for functional food formulation. Antioxidants (Basel). 2021; 10(7):1037. https://doi.org/10.3390/antiox10071037
Prakash MD, Fraser S, Boer JC, Plebanski M, de Courten B, Apostolopoulos V. Anti-Cancer Effects of Carnosine-A Dipeptide Molecule. Molecules. 2021; 26(6):1644. https://doi.org/10.3390/molecules26061644
Kiani AK, Pheby D, Henehan G, Brown R, Sieving P, Sykora P, et al. Ethical considerations regarding animal experimentation. J Prev Med Hyg. 2022; 63(2 Suppl 3):E255-E266. https://doi.org/10.15167/2421-4248/jpmh2022.63.2s3.2768
Yu JB, Lee DS, Padanilam BJ, Kim J. Repeated Administration of Cisplatin Transforms Kidney Fibroblasts through G2/M Arrest and Cellular Senescence. Cells. 2022;11(21):3472. https://doi.org/10.3390/cells11213472
Park J, Jang J, Cha SR, Baek H, Lee J, Hong SH, et al. L-carnosine Attenuates Bleomycin-Induced Oxidative Stress via NFκB Pathway in the Pathogenesis of Pulmonary Fibrosis. Antioxidants (Basel). 2022;11(12):2462. https://doi.org/10.3390/antiox11122462
Tobar Leitão SA, Soares DDS, Carvas Junior N, Zimmer R, Ludwig NF, Andrades M. Study of anesthetics for euthanasia in rats and mice: A systematic review and meta-analysis on the impact upon biological outcomes (SAFE-RM). Life Sci 2021; 284:119916. https://doi.org/10.1016/j.lfs.2021.119916
Krishna M. Histological Grading and Staging of Chronic Hepatitis. Clin Liver Dis (Hoboken). 2021; 17(4):222-226. https://doi.org/10.1002/cld.1014
Sioud F, Ben Toumia I, Lahmer A, Khlifi R, Dhaouefi Z, Maatouk M, et al. Methanolic extract of Ephedra alata ameliorates cisplatin-induced nephrotoxicity and hepatotoxicity through reducing oxidative stress and genotoxicity. Environ Sci Pollut Res Int 2020; 27(11):12792-801. https://doi.org/10.1007/s11356-020-07904-3
Hwang D-B, Won D-H, Shin Y-S, Kim S-Y, Kang B-C, Lim K-M, et al. Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility. Free Radic Biol Med 2020; 148:128-39. https://doi.org/10.1016/j.freeradbiomed.2020.01.003
Zhu T, Li Z, Yuan J, Huang K, Chen G, Guo R, et al. Characteristics of liver volume and pathological changes with different stages of liver fibrosis in chronic liver disease. Zhonghua Gan Zang Bing Za Zhi 2024; 32(6):517-24. https://doi.org/10.3760/cma.j.cn501113-20231219-00286
Esmat MA, Osman A, Hassan RE, Hagag SA, El-Maghraby TK. Hepatoprotective effect of ferulic acid and/or low doses of γ-irradiation against cisplatin-induced liver injury in rats. Hum Exp Toxicol 2022; 41:09603271221136205. https://doi.org/10.1177/09603271221136205
Zhang X, Liu Y, Liu M, Ma Q, Hao Z, Tang S, et al. Ellagic acid supplementation ameliorates cisplatin-induced liver injury in mice by inhibiting the NF-κB pathway and activating the Nrf2/HO-1 pathway. One Health Adv 2024; 2(1):20. https://doi.org/10.1186/s44280-024-00056-w
Liu X-q, Jiang L, Lei L, Nie Z-y, Zhu W, Wang S, et al. Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis. Clin Sci 2020; 134(23):3175-93. https://doi.org/10.1042/cs20201207
Bademci R, Erdoğan MA, Eroğlu E, Meral A, Erdoğan A, Atasoy Ö, et al. Demonstration of the protective effect of ghrelin in the livers of rats with cisplatin toxicity. Hum Exp Toxicol 2021; 40(12):2178-87. https://doi.org/10.1177/09603271211026722
Nimbalkar V, Vyawahare N. L-carnitine Protects Cisplatin-Induced Liver Fibrosis in Experimental Animals via Reducing Oxidative and Nitrosative Stress. Int J Pharmaceut Invest 2022; 12(3):370-4. https://doi.org/10.5530/ijpi.2022.3.62
Mousa AM, Aldebasi YH. L-carnosine mitigates interleukin-1α-induced dry eye disease in rabbits via its antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic effects. Cutan Ocul Toxicol 2021; 40(3):241-51. http://doi:10.1080/15569527.2021.1935995
Chang LT, Lee YL, Yuan TH, Chang JH, Chang TY, Lee CH, et al. Hepatotoxicity caused by repeated and subchronic pulmonary exposure to low-level vinyl chloride in mice. Atmosphere 2021; 12(5):596. https://doi.org/10.3390/atmos12050596

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