Effect of dapagliflozin on rat liver ischemia-reperfusion injury

Document Type : Original Article

Authors

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

Abstract
In recent years, liver transplantation has emerged as the standard therapy for several liver disorders. Throughout the procedure, the transplanted liver tissue is subjected to varying degrees of ischemia-reperfusion (IR) damage. Consequently, there has been a long-standing pursuit of substances that can alleviate the harm caused by IR. In our investigation, we employed dapagliflozin as a potential therapeutic agent. Eighteen Wistar rats were divided into three groups (n = 6), including treatment, IR, and control that did not undergo surgical intervention. Two days prior to surgery, the treatment group received dapagliflozin at a dosage of 10.00 mg kg-1 orally. During surgery, liver ischemia was induced for 1 hr, followed by a 24-hr reperfusion period. The IR group exhibited elevated levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, bilirubin, lactate dehydrogenase, and malondialdehyde compared to the control group. In contrast, the treatment group showed levels of these factors that were closer to those of the control group. While total protein, albumin, and total anti-oxidant capacity decreased in the IR group, this decline was less significant in the treatment group. Analysis of oxidative stress in liver tissue revealed that the treatment group had increased anti-oxidant capacity, and exhibited less oxidative stress compared to the IR group. Furthermore, dapagliflozin was found to reduce the degree of liver edema, necrosis, and vascular hyperemia following IR. Overall, dapagliflozin demonstrates the potential to lessen liver damage, enhance liver tissue regeneration, and mitigate the consequences associated with liver impairment.

Keywords

Subjects


1.     Jafarian A, Kasraianfard A, Najafi A, et al. Patient outcomes in a liver transplant program in Iran. Exp Clin Transplant 2014; 12(Suppl 1): 86-91.
2.     Khademolhosseini F, Malekhosseini SA, Salahi H, et al. Outcome and characteristics of patients on the liver transplant waiting list: Shiraz experience. Middle East J Dig Dis 2009; 1(2): 63-67.
3.     Freeman RB. Deceased donor risk factors influencing liver transplant outcome. Transpl Int 2013; 26(5): 463-470.
4.     Pratschke J, Volk HD. Brain death–associated ischemia and reperfusion injury. Curr Opin Organ Transplant 2004; 9(2): 153-158.
5.     Bonaccorsi-Riani E, Pennycuick A, Londoño MC, et al. Molecular characterization of acute cellular rejection occurring during intentional immunosuppression withdrawal in liver transplantation. Am J Transplant 2016; 16(2): 484-496.
6.     Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol 2010; 25(1): 61-74.
7.     Mohamed ME, Abdelnaby RM, Younis NS. β-caryophyllene ameliorates hepatic ischemia reperfusion-induced injury: the involvement of Keap1/Nrf2/HO 1/NQO 1 and TLR4/NF-κB/NLRP3 signaling pathways. Eur Rev Med Pharmacol Sci 2022; 26(22): 8551-8566
8.     Toledo-Pereyra LH, Simmons RL, Najarian JS. Protection of the ischemic liver by donor pretreatment before transplantation. Am J Surg 1975; 129(5): 513-517.
9.     Teoh NC. Hepatic ischemia reperfusion injury: contemporary perspectives on pathogenic mechanisms and basis for hepatoprotection—the good, bad and deadly. J Gastroenterol Hepatol 2011; 26(s1): 180-187.
10. Weigand K, Brost S, Steinebrunner N, et al. Ischemia/reperfusion injury in liver surgery and transplantation: pathophysiology. HPB Surg 2012; 2012: 176723. doi: 10.1155/2012/176723.
11. Halici Z, Karaca M, Keles ON, et al. Protective effects of amlodipine on ischemia-reperfusion injury of rat ovary: biochemical and histopathologic evaluation. Fertil Steril 2008; 90(6): 2408-2415.
12. Abu‐Amara M, Yang SY, Tapuria N, et al. Liver ischemia/reperfusion injury: processes in inflammatory networks- -a review. Liver Transpl 2010; 16(9): 1016-1032.
13. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284(1): G15-G26.
14. Mendes-Braz M, Elias-Miró M, Jiménez-Castro MB, et al. The current state of knowledge of hepatic ischemia‐reperfusion injury based on its study in experimental models. J Biomed Biotechnol 2012; 2012: 298657. doi: 10.1155/2012/298657.
15. Tokgoz VY, Sipahi M, Keskin O, et al. Protective effects of vitamin D on ischemia-reperfusion injury of the ovary in a rat model. Iran J Basic Med Sci 2018; 21(6): 593-599.
16. Sak ME, Soydinc HE, Sak S, et al. The protective effect of curcumin on ischemia-reperfusion injury in rat ovary. Int J Surg 2013; 11(9): 967-970.
17. Rigattieri S, Buffon A, Ramazzotti V, et al. Oxidative stress in ischemia-reperfusion injury: assessment by three independent biochemical markers. Ital Heart J 2000; 1(1): 68-72.
18. LaRosa DF, Rahman AH, Turka LA. The innate immune system in allograft rejection and tolerance. J Immunol 2007; 178(12): 7503-7509.
19. Hassib ST, Taha EA, Elkady EF, et al. Validated liquid chromatographic method for the determination of (canagliflozin, dapagliflozin or empagliflozin) and metformin in the presence of (1-cyanoguanidine). J Chromatogr Sci 2019; 57(8): 697-707.
20. Chertow GM, Vart P, Jongs N, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol 2021; 32(9): 2352-2361.
21. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004; 27(Suppl 1): S5-S10.
22. Chang YK, Choi H, Jeong JY, et al. Dapagliflozin, SGLT2 inhibitor, attenuates renal ischemia-reperfusion injury. PloS One. 2016; 11(7): e0158810. doi: 10.1371/ journal.pone.0158810.
23. Lahnwong S, Palee S, Apaijai N, et al. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol 2020; 19(1): 91. doi: 10.1186/s12933-020-01066-9.
24. Xiong S, Mo D, Wu Y, et al. The effect of dapagliflozin on myocardial ischemia-reperfusion injury in diabetic rats. Can J Physiol Pharmacol 2023; 101(2): 80-89.
25. Phrueksotsai S, Pinyopornpanish K, Euathrongchit J, et al. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non‐alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36(10): 2952-2959.
26. Park HK, Kang SW, Park MS. Hesperidin ameliorates hepatic ischemia-reperfusion injury in Sprague-Dawley rats. Transplant Proc 2019; 51(8): 2828-2832.
27. Gendy A, Elnagar MR, Soubh A, et al. Morin alleviates hepatic ischemia/reperfusion-induced mischief: in vivo and in silico contribution of Nrf2, TLR4, and NLRP3. Biomed Pharmacother 2021; 138: 111539. doi: 10.1016/j.biopha.2021.111539
28. Zhang S, Feng Z, Gao W, et al. Aucubin attenuates liver ischemia-reperfusion injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, oxidative stress, and apoptosis. Front Pharmacol 2020; 11: 544124. doi: 10.3389/fphar.2020.544124.
29. Golshahi H, Araghi A, Baghban F, et al. Protective effects of 2-methoxycinnamaldehyde an active ingredients of Cinnamomum cassia on warm hepatic ischemia reperfusion injury in rat model. Iran J Basic Med Sci 2019; 22(12): 1400-1407.
30. Lau A, Halliday C, Chen SC, et al. Comparison of whole blood, serum, and plasma for early detection of candidemia by multiplex-tandem PCR. J Clin Microbiol 2010; 48(3): 811-816.
31. Bergmeyer HU, Hørder M, Rej R. International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, EC 2.6. 1.1). J Clin Chem Clin Biochem 1986; 24(7): 497-510.
32. Bergmeyer HU, Hørder M, Rej R. International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-alanine: 2-oxoglutarate aminotransferase, EC 2.6.1.2). J Clin Chem Clin Biochem 1986; 24(7): 481-495.
33. Withold W, Rick W. Evaluation of an immuno-radiometric assay for bone alkaline phosphatase mass concentration in human sera. Eur J Clin Chem Clin Biochem 1994; 32(2): 91-96.
34. Çolak Samsum E, Sürer H, Bolat S, et al. Comparison of lipemia interference created with native lipemic material and intravenous lipid emulsion in emergency laboratory tests. Biochem Med (Zagreb) 2024; 34(2): 020701. doi: 10.11613/BM.2024.020701.
35. Sharif Y, Irshad S, Muazzam A, et al. Assessment of patients with β-thalassemia major, undergoing tertiary care at a regional thalassemia center in Pakistan. Pakistan J Zool 2021; 53(1): 245-250.
36. Javaraiah RK, David CM, Namitha J, et al. Evaluation of salivary lactate dehydrogenase as a prognostic biomarker in tobacco users with and without potentially malignant disorders of the oral cavity. South Asian J Cancer 2020; 9(02): 93-98.
37. Babalola AS, Jonathan J, Michael BE. Oxidative stress and anti-oxidants in asymptomatic malaria-positive patients: a hospital-based cross-sectional Nigerian study. Egypt J Intern Med 2020; 32(1): 23. doi: 10.1186/s43162-020-00024-x.
38. Kambayashi Y, Binh NT, Asakura HW, et al. Efficient assay for total antioxidant capacity in human plasma using a 96-well microplate. J Clin Biochem Nutr 2009; 44(1): 46-51.
39. Hadwan MH. Simple spectrophotometric assay for measuring catalase activity in biological tissues. BMC Biochem 2018; 19(1): 7. doi: 10.1186/s12858-018-0097-5.
40. Cadenas S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med 2018; 117: 76-89.
41. Hascalik S, Celik O, Turkoz Y, et al. Resveratrol, a red wine constituent polyphenol, protects from ischemia- reperfusion damage of the ovaries. Gynecol Obstet Invest 2004; 57(4): 218-223.
42. Sahin T, Begec Z, Toprak Hİ, et al. The effects of dexmedetomidine on liver ischemia–reperfusion injury in rats. J Surg Res 2013; 183(1): 385-390.
43. Köken T, Inal M. The effect of nitric oxide on ischemia-reperfusion injury in rat liver. Clin Chim Acta 1999; 288(1-2): 55-62.
44. Jaeschke H, Smith CV, Mitchell JR. Reactive oxygen species during ischemia-reflow injury in isolated per-fused rat liver. J Clin Invest 1988; 81(4): 1240-1246.
45. Zhu Q, Hao H, Li N, et al. Protective effects and mechanisms of dapagliflozin on renal ischemia/ reperfusion injury. Transpl Immunol 2024; 84: 102010. doi: 10.1016/j.trim.2024.102010.
46. Ferchichi H, Bacha S, Kourda N, et al. Animal model of liver ischemia reperfusion: biochemical and histo-logical evaluation. Tunis Med 2016; 94(3): 235-243.
47. He K, Li J, Xi W, et al. Dapagliflozin for nonalcoholic fatty liver disease: a systematic review and meta- analysis. Diabetes Res Clin Pract 2022; 185: 109791.doi: 10.1016/j.diabres.2022.109791.
48. Aso Y, Jojima T, Iijima T, et al. 132-OR: effects of dapagliflozin, an SGLT2 inhibitor, on hepatic steatosis and fibrosis evaluated by transient elastography in patients with type 2 diabetes and nonalcoholic fatty liver disease. Diabetes 2019; 68(Suppl 1): 132-OR. doi: 10.2337/db19-132-OR.
49. Amouzandeh M, Sundström A, Wahlin S, et al. Albumin and fibrinogen synthesis rates in advanced chronic liver disease. Am J Physiol Gastrointest Liver Physiol 2023; 325(5): G391-G397.
50. Rafferty MJ, McMillan DC, Preston TC, et al. Reprioritisation of liver export protein synthesis in patients with decompensated alcoholic liver disease. J Hepatol Gastroint Dis 2016; 2(3): 1000135. doi: 10.4172/2475-3181.1000135.
51. Lin D, Song Y. Dapagliflozin presented nonalcoholic fatty liver through metabolite extraction and AMPK/ NLRP3 signaling pathway. Horm Metab Res 2023; 55(1): 75-84.
Volume 17, Issue 1
January 2026
Pages 47-55

  • Receive Date 15 January 2025
  • Revise Date 26 March 2025
  • Accept Date 22 April 2025