The effects of agmatine treatment on cisplatin-induced hepatotoxicity: an experimental rat study
Keywords:
Agmatine, Cisplatin, Chemical and drug-induced liver injury, Oxidative stress, Rats, Agmatine treatment, Cisplatin toxicity, Oxidative liver damage, Inflammation, Experimental rat study, HepatoprotectionAbstract
BACKGROUND: Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by dose-dependent hepatotoxicity, primarily driven by oxidative stress and inflammation. Agmatine, an endogenous polyamine, has demonstrated antioxidant and anti-inflammatory properties in various models; however, its hepatoprotective effects in cisplatin-induced liver injury remain underexplored.
METHODS: This experimental study investigated the protective effects of agmatine against cisplatin-induced hepatotoxicity in 28 male Sprague Dawley rats. The animals were randomized into four groups: Sham, Cisplatin, Cisplatin + Agmatine (20 g/kg/day, orally), and Placebo. Biochemical markers, including ALT, AST, MDA (malondialdehyde), SOD (superoxide dismutase), GPx (glutathione peroxidase), TNF-α, IL-1β, and TGF-β, were assessed using ELISA (enzyme-linked immunosorbent assay). Histopathological evaluation was performed to assess liver architecture and injury severity.
RESULTS: Cisplatin administration significantly increased serum levels of ALT, AST, MDA, and proinflammatory cytokines (IL-1β, TNF-α, and TGF-β), while reducing antioxidant enzyme activities (SOD and GPx) (p < 0.01). Agmatine co-administration significantly reversed these biochemical alterations and ameliorated histopathological damage, as evidenced by reduced inflammatory infiltration, sinusoidal dilatation, and hepatocellular degeneration.
CONCLUSION: Agmatine demonstrates significant hepatoprotective effects against cisplatin-induced liver injury by attenuating oxidative stress and inflammatory responses. These findings suggest its potential role as an adjunctive agent to improve the hepatic safety profile of cisplatin chemotherapy.
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1. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014 Oct 5;740:364–78. PMID: 25058905; https://doi.org/10.1016/j.ejphar.2014.07.025.
2. Chovanec M, Abu Zaid M, Hanna N, El-Kouri N, Einhorn LH, Albany C. Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann Oncol. 2017 Nov 1;28(11):2670–9. PMID: 29045502; https://doi.org/10.1093/annonc/mdx360.
3. Qi L, Luo Q, Zhang Y, Jia F, Zhao Y, Wang F. Advances in toxicological research of the anticancer drug cisplatin. Chem Res Toxicol. 2019 Aug 19;32(8):1469–86. PMID: 31353895; https://doi.org/10.1021/acs.chemrestox.9b00204.
4. Christova TY, Gorneva GA, Taxirov SI, Duridanova DB, Setchenska MS. Effect of cisplatin and cobalt chloride on antioxidant enzymes in the livers of Lewis lung carcinoma-bearing mice: protective role of heme oxygenase. Toxicol Lett. 2003 Mar 3;138(3):235–42. PMID: 12565200; https://doi.org/10.1016/s0378-4274(02)00416-2.
5. Waseem M, Bhardwaj M, Tabassum H, Raisuddin S, Parvez S. Cisplatin hepatotoxicity mediated by mitochondrial stress. Drug Chem Toxicol. 2015 Oct;38(4):452–9. PMID: 25678195; https://doi.org/10.3109/01480545.2014.992437.
6. Xu W, Gao L, Li T, Shao A, Zhang J. Neuroprotective role of agmatine in neurological diseases. Curr Neuropharmacol. 2018;16(9):1296–305. PMID: 28786346; https://doi.org/10.2174/1570159X15666170808120633.
7. Kotagale NR, Taksande BG, Inamdar NN. Neuroprotective offerings by agmatine. Neurotoxicology. 2019 Jul;73:228–45. PMID: 31063707; https://doi.org/10.1016/j.neuro.2019.05.001.
8. Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996 May 15;316(Pt 1):247–9. PMID: 8645212; https://doi.org/10.1042/bj3160247.
9. Donertas B, Unel CC, Erol K. Cannabinoids and agmatine as potential therapeutic alternatives for cisplatin-induced peripheral neuropathy. J Exp Pharmacol. 2018 Jun 22;10:19–28. PMID: 29950907; https://doi.org/10.2147/JEP.S162059.
10. Salihoglu YS, Elri T, Gulle K, et al. Evaluation of the protective effect of agmatine against cisplatin nephrotoxicity with 99mTc-DMSA renal scintigraphy and cystatin-C. Ren Fail. 2016 Oct;38(9):1496–502. PMID: 27604130; https://doi.org/10.1080/0886022X.2016.1227919.
11. Xiang Y, Zhou X, Zhou H, et al. Limonin ameliorates cisplatin-induced acute liver injury by inhibiting 11β-hydroxysteroid dehydrogenase type 1. Biomed Pharmacother. 2023 Dec;168:115680. PMID: 37832403; https://doi.org/10.1016/j.biopha.2023.115680.
12. Bekhit AA, Beshay ON, Fawzy MA, et al. Curative effect of AD-MSCs against cisplatin-induced hepatotoxicity in rats is potentiated by azilsartan: targeting oxidative stress, MAPK, and apoptosis signaling pathways. Stem Cells Int. 2023 Oct 23;2023:6767735. PMID: 37908315; https://doi.org/10.1155/2023/6767735.
13. Omar HA, Mohamed WR, Arafa SA, et al. Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity. Pharmacol Rep. 2016 Apr;68(2):349–56. PMID: 26922538; https://doi.org/10.1016/j.pharep.2015.09.007.
14. Waseem M, Pandey P, Tomar B, Raisuddin S, Parvez S. Ameliorative action of curcumin in cisplatin-mediated hepatotoxicity: an in vivo study in Wistar rats. Arch Med Res. 2014 Aug;45(6):462–8. PMID: 25080283; https://doi.org/10.1016/j.arcmed.2014.07.006.
15. Niazvand F, Ashtari A, Chamkouri N, Azari M. Hepatoprotective effects of alpinia officinarum rhizome extract on cisplatin-induced hepatotoxicity in rats: a biochemical, histopathological and immunohistochemical study. J Trace Elem Med Biol. 2023 Dec;80:127306. PMID: 37757646; https://doi.org/10.1016/j.jtemb.2023.127306.
16. Ahmed N, Aljuhani N, Al-Hujaili HS, et al. Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway. J Biochem Mol Toxicol. 2018 Dec;32(12):e22227. PMID: 30273971; https://doi.org/10.1002/jbt.22227.
17. Alharbi N, Nour O, Makled MN, Nader M. Agmatine abrogates tacrolimus-induced testicular injury in rats. Pharmaceutics. 2025 May 27;17(6):703. PMID: 40574016; https://doi.org/10.3390/pharmaceutics17060703.
18. Yeniceri M, Tanoglu A, Salmanoglu M, et al. Efficacy of agmatine treatment in experimental acute pancreatitis rat model. J Gastroenterol. 2024 Jan;35(1):27–31. PMID: 38454275; https://doi.org/10.5152/tjg.2024.23017.
19. Donertas B, Cengelli Unel C, Aydin S, et al. Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats. Fundam Clin Pharmacol. 2018 Jun;32(3):288–96. https://doi.org/10.1111/fcp.12351. Erratum in: Fundam Clin Pharmacol. 2018 Dec;32(6):678. PMID: 29377255; https://doi.org/10.1111/fcp.12429.
20. Izadi S, Rezaei A, Esmaili Z, Soukhaklari R, Moosavi M. Agmatine prevents the memory impairment and the dysfunction of hippocampal GSK-3β and ERK signaling induced by aluminum nanoparticle in mice. Behav Pharmacol. 2023 Aug 1;34(5):299–305. PMID: 37401404; https://doi.org/10.1097/FBP.0000000000000735.
21. Ommati MM, Niknahad H, Najibi A, et al. Cholestasis-associated pulmonary inflammation, oxidative stress, and tissue fibrosis: the protective role of the biogenic amine agmatine. Pharmacology. 2023;108(4):379–93. PMID: 37253339; https://doi.org/10.1159/000530307.
22. Raghavan SA, Dikshit M. Vascular regulation by the L-arginine metabolites, nitric oxide and agmatine. Pharmacol Res. 2004 May;49(5):397–414. PMID: 14998549; https://doi.org/10.1016/j.phrs.2003.10.008.
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