Ginkgo biloba L. extract and flunixin meglumine attenuate sepsis–associated liver injury, oxidative stress, inflammation and apoptosis in rats
Abstract
Lipopolysaccharide (LPS), known as a stimulant of inflammation, causes acute liver injury by inducing the production of inflammatory mediators and oxidative stress. The purpose of this study is to determine whether of a nonsteroidal anti–inflammatory drug (NSAID) Flunixin meglumine (FM) and herbal an medicine Ginkgo biloba L. extract (GBE) show antioxidative, anti–inflammatory or antiapoptotic effects in liver tissue in LPS–induced hepatotoxicity. Animals were separated to 6 groups as control, sepsis (1 mg·kg-1, 7th day single dose, intraperitoneal (ip)), sepsis + FM (1 mg·kg-1, 7th day single dose, ip + 2.2 mg·kg-1 day, ip), sepsis + GBE (1 mg·kg-1, 7th day single dose, ip + 50 mg·kg-1 day, gavage), FM and GBE and the study continued for 7 days. Liver tissues taken from rats sacrificed were analyzed biochemically, histologically and immunohistochemically. Accordingly, LPS caused liver function markers alteration, inflammation, oxidative stress, and apoptosis, as well as histopathological changes in liver tissue. However, it was observed that LPS–induced changes were regulated by FM and GBE application. FM and GBE was demonstrated to have antioxidant, antiinflammatory and anti–apoptotic properties in LPS–induced hepatotoxicity.
Downloads
References
Boé DM, Richens TR, Horstmann SA, Burnham EL, Janssen WJ, Henson PM, Moss M, Vandivier RW. Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response. Alcohol Clin. Exp. Res. [Internet]. 2010; 34(10):1723–1732. doi: https://doi.org/dh5xzz
Kim EA, Kim SY, Ye BR, Kim J, Ko SC, Lee WW, Kim KN, Choi IW, Jung WK, Heo SJ. Anti–inflammatory effect of Apo–90–fucoxanthinone via inhibition of MAPKs and NF–kB signaling pathway in LPS–stimulated RAW 264.7 macrophages and zebrafish model. Int. Immunopharmacol. [Internet]. 2018; 59:339–346. doi: https://doi.org/gdrp4g
Cadenas S, Cadenas AM. Fighting the stranger‑antioxidant protection against endotoxin toxicity. Toxicology [Internet]. 2002; 180(1):45–63. doi: https://doi.org/drzr24
Avila TV, Pereira ALB, Christoff AO, Soley BS, Queiroz–Telles JE, Eler GJ, Bracht A, Zampronio AR, Acco A. Hepatic effects of flunixin–meglumin in LPS–induced sepsis. Fundam. Clin. Pharmacol. [Internet]. 2010; 24(6):759–769. https://https://doi.org/c7z9zx
Radostits OM, Gay CC, Hinchcliff KW, Constable PD. Veterinary medicine: A text book of the diseases of cattle, horses, sheep, pigs and goats. 10th ed. Amsterdam: Saunders Ltd; 2007. Chapter 1, General systemic states. p. 39–124.
Khan HU, Aamir K, Jusuf PR, Sethi G. Sisinthy SP, Ghildyal R, Arya A. Lauric acid ameliorates lipopolysaccharide (LPS)–induced liver inflammation by mediating TLR4/MyD88 pathway in Sprague Dawley (SD) rats. Life Sci. [Internet]. 2021; 265:118750. doi: https://doi.org/g646jq
Wu J, Yan X, Jin G. Ulinastatin protects rats from sepsis–induced acute lung injury by suppressing the JAK–STAT3 pathway. J. Cell Biochem. [Internet]. 2018; 120(2):2554–2559. doi: https://doi.org/gg7gqj
Wang Z, Zhang P, Wang Q, Sheng X, Zhang J, Lu X, Fan X. Protective effects of Ginkgo biloba dropping pills against liver ischemia/reperfusion injury in mice. Chin. Med. [Internet]. 2020; 15(122). doi: https://doi.org/g8wpcz
Liu Y, Xin H, Zhang Y, Che F, Shen N, Cui Y. Leaves, seeds and exocarp of Ginkgo biloba L. (Ginkgoaceae): A comprehensive review of traditional uses, phytochemistry, pharmacology, resource utilization and toxicity. J. Ethnopharmacol. [Internet]. 2022; 298:115645. doi: https://doi.org/gs4g5d
Farzaneh–Omidkhoda S, Marjan–Razavi B, Hosseinzadeh H. Protective effects of Ginkgo biloba L. against natural toxins, chemical toxicities, and radiation: A comprehensive review. Phytother. Res. [Internet]. 2019; 33(11):2821–2840. doi: https://doi.org/gp6vc4
El–Maksoud EMA, Lebda MA, Hashem AE, Taha NM, Kamel MA. Ginkgo biloba mitigates silver nanoparticles–induced hepatotoxicity in Wistar rats via improvement of mitochondrial biogenesis and antioxidant status. Environ. Sci. Pollut. Res. Int. [Internet]. 2019; 26(25):25844–25854. doi: https://doi.org/gwdpk6
Ganesan K, Jayachandran M, Xu B. A critical review on hepatoprotective effects of bioactive food components. Crit. Rev. Food Sci. [Internet]. 2018; 58(7):1165–1229. doi: https://doi.org/g62r6f
Ilhan N, Susam S, Gul HF, Ilhan N. The therapeutic effects of thalidomide and etanercept on septic rats exposed to lipopolysaccharide. Ulus. Travma Acil Cerrahi Derg. [Internet]. 2019; 25(2):99–104. doi: https://doi.org/g8wpc2
Li M, Li B, Hou Y, Tian Y, Chen L, Liu S, Zhang N, Dong J. Anti–inflammatory effects of chemical components from Ginkgo biloba L. male flowers on lipopolysaccharide–stimulated RAW264.7 macrophages. Phytother. Res. [Internet]. 2019; 33(4):989–997. doi: https://doi.org/g8wpc3
Kaur G, Tirkey N, Bharrhan S, Chanana V, Rishi P, Chopra K. Inhibition of oxidative stress and cytokine activity by curcumin in amelioration of endotoxin–induced experimental hepatoxicity in rodents. Clin. Exp. Immunol. [Internet]. 2006; 145(2):313–321. doi: https://doi.org/dfzjwr
Silva GGPd, Zanoni JN, Buttow NC. Neuroprotective action of Ginkgo biloba on the enteric nervous system of diabetic rats. World J. Gastroenterol. [Internet]. 2011; 17(7):898–905. doi: https://doi.org/bqnfhx
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. [Internet]. 1979; 95(2):351–358. doi: https://doi.org/bktx4x
Ellman G. Tissue sulfhydryl groups. Arch. Biochem. Biophys. [Internet]. 1959; 82(1):70–77. doi: https://doi.org/bz2vt8
Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin. Chem. 1988; 34(3):497–500. PMID: 3349599
Aebi H. Catalase in vitro. Methods Enzymol. [Internet]. 1984; 105:121–126. doi: https://doi.org/dnf7v9
Zhang X, Su C, Zhao S, Li J, Yu F. Combination therapy of Ulinastatin with Thrombomodulin alleviates endotoxin (LPS)–induced liver and kidney injury via inhibiting apoptosis, oxidative stress and HMGB1/TLR4/NF–κB pathway. Bioengineered [Internet]. 2022; 13(2):2951–2970. doi: https://doi.org/g8wpc4
Kahramanoğulları M, Erisir M, Yaman M, Parlak–Ak T. Effects of naringenin on oxidative damage and apoptosis in liver and kidney in rats subjected to chronic mercury chloride. Environ. Toxicol. [Internet]. 2024; 39(5):2937–2947. doi: https://doi.org/g8wpc5
Wang M, Feng J, Zhou D, Wang J. Bacterial lipopolysaccharide–induced endothelial activation and dysfunction: a new predictive and therapeutic paradigm for sepsis. Eur. J. Med. Res. [Internet]. 2023; 28(339). doi: https://doi.org/g8wpc6
Al–Dossari MH, Fadda LM, Attia HA, Hasan IH, Mahmoud AM. Curcumin and selenium prevent lipopolysaccharide/diclofenac–ınduced liver injury by suppressing ınflammation and oxidative stress. Biol. Trace Elem. Res. [Internet]. 2020; 196(1):173–83. doi: https://doi.org/g8wpc7
Song H, Zhang X, Zhai R, Liang H, Song G, Yuan Y, Xu Y, Yan Y, Qiu L, Sun T. Metformin attenuated sepsis–associated liver injury and inflammatory response in aged mice. Bioengineered [Internet]. 2022; 13(2):4598–4609. doi: https://doi.org/grqnjr
Beheshti F, Hosseini M, Sarvtin MT, Kamali A, Anaeigoudari A. Protective effect of aminoguanidine against lipopolysaccharide–induced hepatotoxicity and liver dysfunction in rat. Drug Chem. Toxicol. [Internet]. 2021; 44(2):215–221. doi: https://doi.org/nxnz
Killilea M, Kerr DM, Mallard BM, Roche M, Wheatley AM. Exacerbated LPS/GalN–induced liver injury in the stress–sensitive Wistar Kyoto rat is associated with changes in the endocannabinoid system. Molecules [Internet]. 2020; 25(17):3834. doi: https://doi.org/g8wpc8
Al–Kury LT, Dayyan F, Shah FA, Malik Z, Khan–Khalil AA, Alattar A, Alshaman R, Ali A, Khan Z. Ginkgo biloba extract protects against methotrexate–induced hepatotoxicity: a computational and pharmacological approach. Molecules. [Internet]. 2020; 25(11):2540. doi: https://doi.org/gjfxcx
El–Shabasy EA, Amer MAA, Keshk FA, Shabana SM Comparative analysis of the antihepatotoxic effects of Ginkgo biloba leaf extract and Legalon using histological and biochemical techniques. J. Microbiol. Exp. [Internet]. 2022; 10(6):229–236. doi: https://doi.org/g8wpc9
Zhang X, Xiong H, Li H, Cheng Y. Protective effect of taraxasterol against LPS–induced endotoxic shock by modulating inflammatory responses in mice. Immunopharmacol. Immunotoxicol. [Internet]. 2014; 36(1):11–16. doi: https://doi.org/g8wpdb
Wu Y, Zhao M, Lin Z. Pyrroloquinoline quinone (PQQ) alleviated sepsis–induced acute liver injury, inflammation, oxidative stress and cell apoptosis by downregulating CUL3 expression. Bioengineered [Internet]. 2021; 12(1):2459–2468. doi: https://doi.org/g8wpdc
Tatli–Seven P, Gül–Baykalir B, Parlak–Ak T, Seven I, Basak N, Yaman M. The protective effects of propolis and flunixin meglumine on feed intake, antioxidant status and histological parameters in liver and kidney tissues against excess copper in rats. Ankara Univ. Vet. Fak. Derg. [Internet]. 2018; 65(4):395–406. doi: https://doi.org/g8wpdd
Salvemini D, Cuzzocrea S. Oxidative stress in septic shock and disseminated intravascular coagulation. Free Radic. Biol. Med. [Internet]. 2002; 33(9):1173–1185. doi: https://doi.org/bnmnz3
Çimen B, Çimen L, Çetin I, Çetin A. Alpha–lipoic acid alleviates lipopolysaccharide–induced liver damage in rats via antioxidant effect. Dicle Tip Derg. [Internet]. 2019; 46(1):125–132. doi: https://doi.org/g8wpdf
Parimoo HA, Sharma R, Patil, RD, Sharma OP, Kumar P, Kumar N. Hepatoprotective effect of Ginkgo biloba leaf extract on lantadenes‐induced hepatotoxicity in guinea pigs. Toxicon [Internet]. 2014; 81:1–12. doi: https://doi.org/f5w4sg
Arab–Nozari M, Ahangar N, Mohammadi E, Lorigooini Z, Shokrzadeh M, Amiri FT, Shaki F. Ginkgo biloba attenuated hepatotoxicity induced by combined exposure to cadmium and fluoride via modulating the redox imbalance, Bax·Bcl–1–2 and NF–kB signaling pathways in male rats. Mol. Biol. Rep. [Internet]. 2020; 47(9):6961–6972. doi: https://doi.org/gkkq43
Li XK, Yang SC, Bi L, Jia Z. Effects of dexmedetomidine on sepsis–induced liver injury in rats. Eur. Rev. Med. Pharmacol. Sci. [Internet]. 2019; 23(Suppl. 3):177–183. doi: https://doi.org/g8wpdg
Baliutyte G, Baniene R, Trumbeckaite S, Borutaite V, Toleikis A. Effects of Ginkgo biloba extract on heart and liver mitochondrial functions: mechanism(s) of action. J. Bioenerg. Biomembr. [Internet]. 2010; 42(2):165–172. doi: https://doi.org/cn92nb
Wang Y, Gao LN, Cui YL, Jiang HL. Protective effect of danhong injection on acute hepatic failure induced by lipopolysaccharide and d‑galactosamine in mice. Evid. Based Complement. Alternat. Med. [Internet]. 2014; 2014:153902. doi: https://doi.org/gbfvz6
Wang Y, Wang R, Wang Y, Peng R, Wu Y, Yuan Y. Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF–κB/IκBα, and Bcl–2/Bax signaling. Drug Des. Devel. Ther. [Internet]. 2015; 9:6303–6317. doi: https://doi.org/g8wpdh

Copyright (c) 2024 Tuba Parlak Ak, Burcu Gul, Mine Yaman, Ismail Seven, Gurdal Dagoglu, Huseyin Fatih Gul

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.