Asma MAHFOUDH BOUSSAID, Rabi SELMI, Kaouther HADJ AYED, Mohamed Amine ZAOUALI, Hassen BEN ABDENNEBI, Mohamed BEJAOUI

Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

Background/aim: The aim of this study was to compare the effects of single and repeated trimetazidine (TMZ) administration against warm hepatic ischemia/reperfusion (I/R) injury and to explore the possible mechanisms affected by TMZ. Materials and methods: Wistar rats were divided into 4 groups (n = 6). Sham: rats were subjected to dissection. I/R: rats were subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. TMZ1: Same as I/R group but rats were pretreated with a single dose of TMZ (10 mg/kg, intraperitoneal injection) 30 min before warm ischemia. TMZ3: Same as I/R but rats were treated with 10 mg/ kg TMZ for 3 successive days. Results: TMZ treatment decreased liver injury, lipid peroxidation, and apoptosis. The repeated administration of TMZ conferred more protection than the single dose treatment concerning all studied parameters. In parallel, we noted a significant increase in phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) and endothelial nitric oxide synthase (eNOS) levels in TMZ3 as compared to TMZ1. Conclusion: Repeated administration of TMZ for 3 days was more efficient than a single dose of TMZ in protecting the liver against I/R induced apoptosis and lipid peroxidation. These effects implicate AMPK and eNOS activation.

PDF

___

1. Shen M, Lu J, Dai W, Wang F, Xu L, Chen K, He L, Cheng P, Zhang Y, Wang C et al. Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy. Mediators Inflamm 2013; 2013: 461536-461548.
2. Akhtar MZ, Henderson T, Sutherland A, Vogel T, Friend PJ. Novel approaches to preventing ischemia-reperfusion injury during liver transplantation. Transplant Proc 2013; 45: 2083- 2092.
3. Rolo AP, Teodoro JS, Peralta C, Rosello-Catafau J, Palmeira CM. Prevention of I/R injury in fatty livers by ischemic preconditioning is associated with increased mitochondrial tolerance: the key role of ATPsynthase and mitochondrial permeability transition. Transpl Int 2009; 22: 1081-1090.
4. Zhang PL, Lun M, Teng J, Huang J, Blasick TM, Yin L, Herrera GA, Cheung JY. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann Clin Lab Sci 2004; 34: 449-457.
5. Iskesen I, Saribulbul O, Cerrahoglu M, Var A, Nazli Y, Sirin H. Trimetazidine reduces oxidative stress in cardiac surgery. Circ J 2006; 70: 1169-1173.
6. Jayle C, Favreau F, Zhang K, Doucet C, Goujon JM, Hebrard W, Carretier M, Eugene M, Mauco G, Tillement JP. Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model. Am J Physiol Renal Physiol 2007; 292: F1082-1093.
7. Zhang Q, Fu H, Zhang H, Xu F, Zou Z, Liu M, Wang Q, Miao M, Shi X. Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3β signaling and inhibiting mitochondrial permeability transition. PLoS One 2013; 8: e74422.
8. Sulikowski T, Domanski L, Ciechanowski K, Adler G, Pawlik A, Safranow K, Dziedziejko V, Chlubek D, Ciechanowicz A. Effect of trimetazidine on xanthine oxidoreductase expression in rat kidney with ischemia-reperfusion injury. Arch Med Res 2008; 39: 459-462.
9. Khan M, Meduru S, Mostafa M, Khan S, Hideg K, Kuppusamy P. Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther 2010; 333: 421-429.
10. Tsimoyiannis EC, Moutesidou KJ, Moschos CM, Karayianni M, Karkabounas S, Kotoulas OB. Trimetazidine for prevention of hepatic injury induced by ischaemia and reperfusion in rats. Eur J Surg 1993; 159: 89-93.
11. Settaf A, Zaim N, Bellouch M, Tillement JP. Trimetazidine prevents ischemia-reperfusion injury in hepatic surgery under vascular clamping. Therapie 2001; 56: 569-574.
12. De Graaf W, Heger M, Spruijt O, Maas A, de Bruin K, Hoekstra R, Bennink RJ, van Gulik TM. Quantitative assessment of liver function after ischemia-reperfusion injury and partial hepatectomy in rats. J Surg Res 2012; 172: 85-94.
13. Ben Mosbah I, Rosello J, Franco-gou R, Ben Abdennebi H, Saidane D, Ramella-virieux S, Boillot O, Peralta C. Preservation of wteatotic livers in IGL-1 solution. Liver Transplant 2006; 12: 1215-1223.
14. Elimadi A, Settaf A, Morin D, Sapena R, Lamchouri F, Cherrah Y, Tillement JP. Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial function. J Pharmacol Exp Ther 1998; 286: 23- 28.
15. Fang H, Liu A, Dahmen U, Dirsch O. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase. Cell Death Dis 2013; 4: e694.
16. Hirakawa A, Takeyama N, Nakatani T, Tanaka, T. Mitochondrial permeability transition and cytochrome c release in ischemiareperfusion injury of the rat liver. J Surg Res 2003, 111: 240- 247.
17. Cau J, Favreau F, Tillement JP, Lerman LO, Hauet T, Goujon JM. Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: a dose effect study. J Vasc Surg 2008; 47: 852-860.
18. Wu Q, Qi B, Liu Y, Cheng B, Liu L, Li Y, Wang Q. Mechanisms underlying protective effects of trimetazidine on endothelial progenitor cells biological functions against H2 O2 -induced injury: involvement of antioxidation and Akt/eNOS signaling pathways. Eur J Pharmacol 2013; 707: 87-94.
19. Matsui Y, Kyoi S, Takagi H, Hsu C, Hariharan N, Ago T, Vatner SF, Sadoshima J. Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion. Autophagy 2008; 4: 409-415.
20. Mount PF, Hill RE, Fraser SA, Levidiotis V, Katsis F, Kemp BE, Power DA. Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOSSer 1177. Am J Physiol Ren Physiol 2005; 289: 1103-1015.
21. Bejaoui M, Zaouali MA, Folch-Puy E, Pantazi E, Bardag-Gorce F, Carbonell T, Oliva J, Rimola A, Abdennebi HB, Roselló- Catafau J. Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways. J Pharm Pharmacol 2014; 66: 62-72.
22. Bouma H, Ketelaar M, Yard B, Ploeg RJ, Henning RH. AMPactivated protein kinase as a target for preconditioning in transplantation medicine. Transplantation 2010; 90: 353-358.
23. Kim MY, Lim JH, Youn HH, Hong YA, Yang KS, Park HS, Chung S, Ko SH, Shin SJ, Choi et al. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice. Diabetologia 2013; 56: 204-217.
24. Zaouali MA, Boncompagni E, Reiter RJ, Bejaoui M, Freitas I, Pantazi E, Folch-Puy E, Abdennebi HB, Garcia-Gil FA, Roselló- Catafau J. AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail. J Pineal Res. 2013; 55: 65-78.
25. Abu-Amara M, Yang SY, Seifalian A, Davidson B, Fuller B. The nitric oxide pathway-evidence and mechanisms for protection against liver ischaemia reperfusion injury. Liver Int 2012; 32: 531-543