The decreasing effect of troxerutin on the level of pro-inflammatory cytokines in rats with sepsis caused by the experimental cecal puncture

Document Type : Research Article


1 Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.

2 Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran.


Sepsis is the main mortality factor in patients undergoing surgery and its treatment currently includes cardiac resuscitation and reducing the immediate risk of infection. Troxerutin is a common compound in vegetables, fruits, and seeds and has several biological activities, including anti-platelet, anti-serotonin, antioxidant, and anti-inflammatory effects. Accordingly, we hypothesized that it can decrease interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-a) levels in the serum of rats with sepsis. Twenty-four adult male Sprague-Dawley rats were used in this study. The rats were equally and randomly divided into 3 groups: sham operation group, control group, and treatment group. Both the control and treatment groups underwent surgical cecal ligation and perforation. Troxerutin (130 mg/kg) was injected subcutaneously twice a day to the animals of the treatment group for 3 days or until the animals’ death. Surviving rats were euthanized after 1.5 ml of blood samples were taken 3 days after the cecal ligation and perforation. IL-1 and TNF-a were measured by the blood serum ELISA assay. The differences in mortality rates were significant between the control group and the other two groups (p = 0.008). The results showed a significant increase in IL-1 and TNF-a in the control group compared to the sham group (p < 0.05). In addition, the levels in the treatment group significantly decreased compared to the control group (p < 0.05). In conclusion, our results indicate that troxerutin could increase survival in rats developing septic shock by reducing pro-inflammatory cytokines including IL-1 and TNF-a.


1.    Yeh SL, Lai YN, Shang HF, Lin MT, Chen WJ. Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis. British Journal of Nutrition. 2004; 91(3):423-9.
2.    Marton A, Kolozsi C, Kusz E, Olah Z, Letoha T, Vizler C, Pecze L. Propylene-glycol aggravates LPS-induced sepsis through production of TNF-α and IL-6. Iranian Journal of Immunology. 2014; 11(2):113-22. 
3.    Carrillo‐Vico A, Lardone PJ, Naji L, Fernández‐Santos JM, Martín‐Lacave I, Guerrero JM, Calvo JR. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro‐/anti‐inflammatory cytokine network, protection against oxidative damage and anti‐apoptotic effects. Journal of Pineal Research. 2005; 39(4):400-8. 
4.    Zhang D, Chen L, Li S, Gu Z, Yan J. Lipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-1β, TNF-α and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS. Innate Immunity. 2008; 14(2):99-107.
5.    Polat G, Ugan RA, Cadirci E, Halici Z. Sepsis and Septic Shock: Current Treatment Strategies and New Approaches. The Eurasian Journal of Medicine. 2017; 49(1):53-8.
6.    Angus DC, Van der Poll T. Severe sepsis and septic shock. New England Journal of Medicine. 2013; 369:840-51. 
7.    Mason PE, Al-Khafaji A, Milbrandt EB, Suffoletto BP, Huang DT. Corticus: The end of unconditional love for steroid use? Critical Care. 2009; 13(4):309.
8.    Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF. Hydrocortisone therapy for patients with septic shock. New England Journal of Medicine. 2008; 358(2):111-24.  
9.    Angus DC. The search for effective therapy for sepsis: back to the drawing board? Journal of the American Medical Association. 2011; 306(23):2614-5.
10.    Webster NR, Galley HF. Immunomodulation in the critically ill. British Journal of Anaesthesia. 2009; 103(1):70-81.
11.    Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D. Drotrecogin alfa (activated) in adults with septic shock. New England Journal of Medicine. 2012; 366(22):2055-64. 
12.    Dehnamaki F, Karimi A, Pilevarian AA, Fatemi I, Hakimizadeh E, Kaeidi A, Allahtavakoli M, Rahmani MR, Khademalhosseini M, Bazmandegan G. Treatment with troxerutin protects against cisplatin-induced kidney injury in mice. Acta Chirurgica Belgica. 2019; 119(1):31-7. 
13.    Schuller‐Petrovic S, Wolzt M, Böhler K, Jilma B, Eichler HG. Studies on the effect of short‐term oral dihydroergotamine and troxerutin in patients with varicose veins. Clinical Pharmacology & Therapeutics. 1994; 56(4):452-9. 
14.    Badalzadeh R, Layeghzadeh N, Alihemmati A, Mohammadi M. Beneficial effect of troxerutin on diabetes-induced vascular damages in rat aorta: histopathological alterations and antioxidation mechanism. International Journal of Endocrinology and Metabolism. 2015; 13(2):e25969.
15.    Gui Y, Li A, Chen F, Zhou H, Tang Y, Chen L, Chen S, Duan S. Involvement of AMPK/SIRT1 pathway in anti-allodynic effect of troxerutin in CCI-induced neuropathic pain. European Journal of Pharmacology. 2015; 769:234-41.
16.    Najafi M, Noroozi E, Javadi A, Badalzadeh R. Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium. Biomedicine & Pharmacotherapy. 2018; 102:385-91. 
17.    Vidhya R, Anuradha CV. Anti-inflammatory effects of troxerutin are mediated through elastase inhibition. Immunopharmacology and Immunotoxicology. 2020; 42(5):423-35. 
18.    Babri S, Mohaddes G, Feizi I, Mohammadnia A, Niapour A, Alihemmati A, Amani M. Effect of troxerutin on synaptic plasticity of hippocampal dentate gyrus neurons in a β-amyloid model of Alzheimer s disease: an electrophysiological study. European Journal of Pharmacology. 2014; 732:19-25.
19.    Shan Q, Zhuang J, Zheng G, Zhang Z, Zhang Y, Lu J, Zheng Y. Troxerutin reduces kidney damage against BDE-47-induced apoptosis via inhibiting NOX2 activity and increasing Nrf2 activity. Oxidative Medicine and Cellular Longevity. 2017. 
20.    Wang Y, Wei S, Chen L, Pei J, Wu H, Pei Y, Chen Y, Wang D. Transcriptomic analysis of gene expression in mice treated with troxerutin. PloS One. 2017; 12(11):e0188261. 
21.    Redondo-Calvo FJ, Montenegro O, Padilla-Valverde D, Villarejo P, Baladrón V, Bejarano-Ramírez N, Galán R, Gómez LA, Villasanti N, Illescas S, Morales V. Thiosulfinate-Enriched Allium sativum Extract as an Adjunct to Antibiotic Treatment of Sepsis in a Rat Peritonitis Model. Applied Sciences. 2021; 11(11):4760. 
22.    Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005; 365(9453):63-78.
23.    Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaut P. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. Journal of the American Medical Association. 2002; 288(7):862-71. 
24.    Temmesfeld-Wollbrück B, Brell B, Dávid I, Dorenberg M, Adolphs J, Schmeck B, Suttorp N, Hippenstiel S. Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock. Intensive Care Medicine. 2007; 33(4):703-10. 
25.    Taniguchi T, Kurita A, Kobayashi K, Yamamoto K, Inaba H. Dose-and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats. Journal of Anesthesia. 2008; 22(3):221-8. 
26.    Chang L, Du JB, Gao LR, Pang YZ, Tang OS. Effect of ghrelin on septic shock in rats. Acta Pharmacologica Sinica. 2003; 24(1):45-9.
27.    Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997; 112(1):235-43. 
28.    Van der Poll T, Opal SM. Host–pathogen interactions in sepsis. Lancet Infectious Diseases. 2008; 8(1):32-43. 
29.    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. 
30.    Tamayo E, Fernández A, Almansa R, Carrasco E, Heredia M, Lajo C, Goncalves L, Gómez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF. Pro-and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. European Cytokine Network. 2011; 22(2):82-7. 
31.    Zhang ZF, Fan SH, Zheng YL, Lu J, Wu DM, Shan Q, Hu B. Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose. Journal of Agricultural and Food Chemistry. 2009; 57(17):7731-6.
32.    Jafari-Khataylou Y, Emami SJ, Mirzakhani N. Troxerutin attenuates inflammatory response in lipopolysaccharide-induced sepsis in mice. Research in Veterinary Science. 2021; 135:469-78. 
33.    Shan Q, Zheng GH, Han XR, Wen X, Wang S, Li MQ, Zhuang J, Zhang ZF, Hu B, Zhang Y, Zheng YL. Troxerutin protects kidney tissue against BDE-47-induced inflammatory damage through CXCR4-TXNIP/NLRP3 signaling. Oxidative Medicine and Cellular Longevity. 2018:1-11. 
34.    Hoseindoost M, Alipour MR, Farajdokht F, Diba R, Bayandor P, Mehri K, Rad SN, Babri S. Effects of troxerutin on inflammatory cytokines and BDNF levels in male offspring of high-fat diet fed rats. Avicenna Journal of Phytomedicine. 2019; 9(6):597. 
35.    Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF, Li MQ. Troxerutin counteracts domoic acid–induced memory deficits in mice by inhibiting CCAAT/enhancer binding protein β–mediated inflammatory response and oxidative stress. The Journal of Immunology. 2013; 190(7):3466-79. 
36.    Zhang ZF, Zhang YQ, Fan SH, Zhuang J, Zheng YL, Lu J, Wu DM, Shan Q, Hu B. Troxerutin protects against 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD+-depletion. Journal of Hazardous Materials. 2015; 283:98-109. 
37.    Liu F, Huang Y, Fu P. Involvement of inflammation-related microRNAs: miR-155 and miR-146a in diabetic nephropathy: Implication in inflammation mediated endothelial injury. Nephrology Dialysis Transplantation. 2012; 27:34-5. 
38.    Yavari R, Badalzadeh R, Alipour MR, Tabatabaei SM. Modulation of hippocampal gene expression of microRNA-146a/microRNA-155-nuclear factor-kappa B inflammatory signaling by troxerutin in healthy and diabetic rats. Indian Journal of Pharmacology. 2016; 48(6):675. 
39.    Ozer J, Levi T, Golan-Goldhirsh A, Gopas J. Anti-inflammatory effect of a Nuphar lutea partially purified leaf extract in murine models of septic shock. Journal of Ethnopharmacology. 2015; 161:86-91. 
40.    Qin X, Jiang X, Jiang X, Wang Y, Miao Z, He W, Yang G, Lv Z, Yu Y, Zheng Y. Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge. Scientific Reports. 2016; 6(1):1-3. 
41.    Chen X, Feng Y, Shen X, Pan G, Fan G, Gao X, Han J, Zhu Y. Anti-sepsis protection of Xuebijing injection is mediated by differential regulation of pro-and anti-inflammatory Th17 and T regulatory cells in a murine model of polymicrobial sepsis. Journal of Ethnopharmacology. 2018; 211:358-65.
42.    Lippi G, Danese E, Cervellin G, Montagnana M. Laboratory diagnostics of spontaneous bacterial peritonitis. Clinica Chimica Acta. 2014; 430:164-70.
43.    Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue III LW, Bland KI, Chaudry IH. Cecal ligation and puncture. Shock. 2005; 24:52-7.
44.    Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nature Protocols. 2009; 4(1):31-6.
45.    Murando F, Peloso A, Cobianchi L. Experimental abdominal sepsis: sticking to an awkward but still useful translational model. Mediators of Inflammation. 2019:1-8.